While I do worry about the state of the FDA and prescription drugs in the US, things like this make me feel glad that drug companies have a well regulated process to catch issues like this before they can become more widespread.
It's all the supplements and other homeopathic exemption stuff that worries me. Not only do they not have to prove they're effect (at all, let alone more effective than the standard treatment), but they've had serious safety issues in the past. Ephedra is a classic example. Plus there are so many times people do tests that find supplements don't contain what they claim.
> things like this make me feel glad that drug companies have a well regulated process to catch issues like this before they can become more widespread.
This is France we're talking about here, we are one of the most regulated country on the planet, this includes FDA like institutions. Still, this could happen anywhere. Also, as has been pointed elsewhere, too much regulation can make people die that could have benefited from the a cure, except we don't notice these death.
Right, it seems like this is a tragic success of the process. Without a body like the FDA or France's equivalent enforcing rigorous trials, this would not be 6 people who opted in, this would be hundreds or thousands of sick people who were harmed.
But yeah, striking the balance between progress and safety is tough. It's just sort of comforting to see a tragedy minimized by the controls we've put in place.
"British regulators approved the trial in just 17 days, and the testing company, based in Massachusetts, did not have an adequate response plan in the event of a disastrous adverse reaction, British investigators concluded."
The unfortunate nature of the seen and the unseen is that we will always notice the times we approved a drug too early or tested too aggressively, but we will never notice the deaths that happen because we were too timid or cautious in our approach.
While this case should be studied to ascertain whether process changes could prevent it, the solution is absolutely not further testing, control, and regulation. Hundreds of thousands of people already die or suffer every year because of the paternalistic, conservative policies governing medicine.
The solution may very well be more testing, control, and regulation.
But there's a difference between minor tweaks to address the root causes of this issue (hypothetical: maybe the drug got contaminated in transit and post-shipping verification of contents needs to be done) and a "Shut it down, shut it all down" reaction.
To draw a thin (but perhaps appropriate analogy): after the hijackings of airplanes on September 11th, the United States responded by expanding the air marshall program, significantly jacking up security and restrictions on passengers, and putting combination locks on airplane cabins. Only the last policy, I think, is actually necessary to address what happened on September 11th, and it's all they should have done.
Personally, I like the idea of air marshalls as well. It makes feel safer while flying. The TSA, on the other hand, definitely makes me feel less safe.
I hate how politicians pander to the base with vague promises to increase or decrease regulation instead of debating to find which regulations are the most effective. Same situation for welfare programs, use of military power overseas, and taxation. There are undoubtedly better ways to use or collect the resources government currently has or even do more with less but they are never considered.
This is pretty much where gun control is right now. Obama was in 'tears' using the Sandy Hook shooting to justify his executive orders, but those executive orders changed nothing that would've prevented the shooting from occurring. The shooter hadn't gotten his weapons through the supposed/alleged 'gun show loophole', for example.
It just lets him claim he 'did something', and makes the base democratic voters happy.
That's a blanket statement with no supporting argument? How about toasters? How about kitchen knives? Knives actually were controlled devices in many nations.
In America, there's this confounding problem of that Amendment. To change anything, that's got to change too.
It certainly isn't here in Illinois, yet gun violence certainly isn't any better here. But the point is, the political rhetoric was completely disingenuous, and unrelated to the laws in question.
We need to fix our violence problem, nobody disagrees about this. But it seems like many Democrats, like Obama, are convinced the only right way to do that is making it more difficult for gun owners to buy guns.
Rather than say, targeting actual problems with a clearly defined link to the crime: Many school shooters steal guns from family members. If Obama actually wanted to reduce shootings, he'd look into how to solve that, rather than pursuing a party agenda instead.
I'd argue mass shootings themselves are a red herring when considering gun deaths. While horrific, the vast majority of gun homicide deaths are handgun crimes that make the local frontpage at best. The Cure Violence program has demonstrated ~30% reductions in gangland shootings and doesn't even require more gun control, but the debate is totally focused on assault rifles and high capacity magazines.
If you actually look at lives saved from each years new drugs per year it's vastly smaller than drug related deaths in that year. We might push back a few months or toss caution to the wind and add ~2 years, but the costs in lives and healthy would be very high.
Where do you draw the line?
PS: Prescription drugs already make some top ten killers lists in the US, there far less safe than generally assumed.
Depends, an estimated 50% of prescribed drugs are proving zero benefit to the patent. Doctors frequently just pick something to get people out of their offices.
So, misuse by someone is very high, but hard to pin down.
I know opiate addiction and death is a real problem, but do you have a source for the "kills more than saves per year" claim? I've never heard that before.
They are very different numbers. A small number of new drugs get on the market every year vs. every drug that ever entered the market.
One way of comparing these numbers is to look at changes in life expectancy. But that changes very slowly suggesting minimal change per year from one years new drugs. Actual deaths from prescription drugs are also hard to measure, but generally assumed at well over 20,000 per year. http://www.voxeu.org/article/genuine-innovation-new-drugs-sa...
Call it ~6-12 months lost vs. ~1-2 months gained. Though the clear upside is those gains should stack year over year. Just not when you compare introducing drugs a few months early as they would have made it to the market anyway.
PS: The clear conflict of interest is the fairly short lifespan of drug patents.
If there's any evidence that the 20k deaths per annum from prescription drugs come mostly from the development of new drugs, you haven't presented it.
What you have presented is evidence that net of deaths from drugs, each year's new drugs offer an extra 2 months of life expectancy to those living in developed countries. By inference, a new regime which uniformly imposed a six month delay to drug development would cost a net 1 month of life expectancy per person. Across a population the size of the US, that's over 300 million months of human life expectancy, or an order of magnitude more whole human lives than your figure for all prescription drug deaths...
If you approve a bad new drug it's not just killing people for just one year. Opiates for example have been in use and killing people for a long time. Arguably, every drug death is a cost from approving some drug at some point in the past.
It's true approving nothing would cost more lives, but that does not mean defaulting to accepting everything is a good idea either. After-all, Opiates are not known as a life saving drug, even if they prevent a lot of pain.
Thus, the 20k+ or ~1% of all deaths are part of the accepted costs for our current system. Don't forget there are plenty of drugs that are not associated with any deaths.
You have to prove a drug saves or improves lives to get it approved in the first place. With the help of survival analysis and clinical trials, we most certainly can quantify it.
You would see an increase in lifespan. Let's put it this way, if 2001 drug save X(1) lives per year and 2002 drugs save X(2) live per year and 2003... Then in 2020 drugs in total are saving X(1) + X(2) + X(3)... lives per year which extends lifespans. So, you would see clear and stacking lifespan increase.
My statement is that on average X(n) is clearly well under 20,000. So, plenty of caution is warranted.
It's not hard to figure out how many lives are saved. Take a look at AIDS for example. 1.2M people in the US have the disease. Since AIDS is now a chronic, non-fatal illness, AIDS drugs have saved at least 1.2M lives.
Medical research is conservative, cautious, and regulated because we strive to move beyond the ugly abuses of our past[2]. It should not be the Wild West.
For insight into modern medical ethics, read the Belmont Report[3]. It's what contemporary researchers must read before conducting any studies involving human subjects. Where I work, we're tested on it.
(This is opinion, but...) Harm today is in research guided more by profit than by benefit. Chronic disease is more profitable than cures or prevention. With rapidly-emergent antibiotic resistance there is little private incentive to develop new antibiotics. We must rely on and expand research in the public interest (funded by NIH, philanthropy, and so on) to balance private biomedical research.
As kauffj eludes to though, it's also worth considering the implicit harm done through inaction. It should not be the wild west, but conversely, articles like this are indicative of a bias toward increasing prevention of active, explicit harm at the expense of more unseen, implicit harm through inaction.
A happy medium is good, but I'd say that that "medium" falls closer to the conservative side.
A lot of the value of "First, do no harm" comes from the point that we have a bias toward action over inaction. Humans, including doctors, want the ability to control our futures. So the temptation is constantly to do something instead of saying "well, that sucks, but we don't have strong reason to believe anything we do will substantially improve things." That's why we perform way too many interventions (particularly, invasive and surgical ones) that at best marginally improve average outcomes at incredible cost and substantial risk. Doctor and patient both want a magic fix. And all too often the fix is more harmful than helpful to the individual patient, even if on average it might be slightly beneficial.
Obviously there's a place for heroic surgical efforts and research into exotic drugs. But we over invest in those compared to the alternatives of prevention and palliation. Conservatism is useful in medicine.
For sure. I don't have a strong opinion either way on whether medicine is too conservative or liberal right now, which probably means it falls within the happy medium ground for some reasonable definition.
Mainly, I think it's worthwhile to point out what appears to be dogma on both sides of any debate.
There's a recent study [1] that shows that outcome for cardiac emergency patients are better (way better) when they're treated at a (good) hospital while the top cardiologists were away (at a conference).
That is, patient outcome is better for patients who go to a hospital with a good reputation, that has outstanding doctors (a teaching hospital) -- but the outcome is best when the top doctors are NOT present in the hospital when the patient checks in.
After controlling for many variables, the only explanation the authors of the study came up with to explain this apparent paradox, is that top doctors want to try anything, esp. the latest procedure/drug, while non-top doctors are more conservative.
At least in the short term, being conservative saves lives.
I don't think we need to group medicine as one thing that is too risk or conservative. We need to evaluate different branches of medicine. In the current culture, we have a bias to accept more risk from surgery than pharmaceuticals.
Imagine you want to be appear more muscular. You could get implants under general anesthesia or you could take steroids. The first is legal, but the second is illegal. It is illegal because society deems that taking steroids is excessively risky. However general anesthesia and surgery are orders of magnitude more dangerous.
This same bias present throughout medicine. Many surgical procedures and tests would never pass the FDA's requirements for pharmaceuticals.
It's entirely possible that medicine would still be conservative, cautious, and regulated after becoming less conservative, cautious and/or regulated, depending on it's starting state. It's important to regularly assess whether a policy is too conservative or not conservative enough, as it's trivial to show that neither extreme is as useful as the middle ground.
One thing is to be cautious in the medical advice you give to a patient. Another is to legally prohibit the patient from taking bigger risks. The idea that anyone but myself has authority over what goes into my body is absolutely ridiculous.
> The idea that anyone but myself has authority over what goes into my body is absolutely ridiculous.
Casting this as a ridiculous argument completely ignores the viewpoint that there may well be externalities caused by this behavior that don't necessarily affect the individual but do affect other individuals. If we take as an example the consumption of illegal drugs the argument can be made that it should be the choice of the individual and not restricted by society, however there is a potential for significant costs (due to the behavior of the individual when under the influence of the drug) that are placed onto the society, thus the subsequent restrictions placed on the individuals.
To be clear I am not intending to debate drug policy or be an apologist for the current war on drugs. My point is to illustrate that a perspective that considers the externalities of a behavior is not a ridiculous position to take as you assert.
I'd say that drug prohibition is ridiculous. It's not only an attack on people's freedom, but also a boon to organized crime and terrorism. A lot of people are willing to pay a lot of money for the product, so if the government stops honest businesses from selling it, the guys with the guns will step in.
The entire thrust of our medical regulatory system, from the Flexner Report to today, is the belief that it's better for 1000 patients to die of neglect, than 1 from quackery. Until this irrational fear of quack medicine is cured, there will be no real progress in the field.[1]
Blindly applying "do no harm" to drug trials ignores opportunity cost. You can kill many thousands of people by delaying the release of a drug for a few months.
This seems to go back to the question of if inaction is an action (or if it counts as partial action). If acting causes harm, but stops greater harm, does it count as more or less harm than not acting? I've never seen a definite answer either way.
Depends on your values, if you go "cold hearted" and say each life is worth as much, the mathematics are rather simple. Add morality, religion, and philosophy to the mix, and you are out of luck.
I'm really surprised that this is news, or that it's being upvoted on HN. Apparently deaths during trials are really rare. From the article:
>A meta-analysis of non-cancer Phase 1 drug trials, published last year in The British Medical Journal, found serious adverse events in only 0.31 percent of participants, and no life-threatening events or deaths.
And the last event comparable to this, according to the article, happened in 2006 in a different country.
I was surprised by this. I would not have expected drug trials to be risk free, in fact I thought that was the whole point. Apparently they are already super conservative and safe. I'm not sure why people are alarmed or calling for more regulation.
It's probably impossible to 100% safety, and certainly not desirable. Parent comment is definitely right that we kill more people through inaction and need to be far more liberal. Total lives saved is all that should matter.
Somehow one person dying out of many drug trials over many years is news that's on the front page of HN. But the 22,000 people that died of cancer today isn't.
Part of the issue is, medically, we (where we = the medical community) killed those people, whereas cancer killed the other 22,000.
Medical ethics are expressly meant to protect subjects from experimentation purely on the basis of "This will probably help more people than it hurts." Given the events that prompted the development of those guidelines, I'm not sure they're wrong.
Because it very, very easily goes some very dark places, especially when you start talking about extreme risk to one person versus a diffuse benefit over several million.
Because people are actually kind of shitty at estimating probabilities, and overconfidence in this area is likely to kill or injure a lot of people. I'm a utilitarian by temperament, but a deontologist in practice because I'm aware that my powers of foresight are actually quite limited and I will very rarely be presented with neatly predictable conflicting imperatives as in the trolley problem. Many self-professed utilitarians wildly overestimate their own intellectual and analytical abilities and come to grief on the rocks of failed predictions. Unfortunately this also tends to involve a lot of innocent casualties too.
On a case by case basis you might have a point, but over time we have tons of statistics on how many drug trials fail and hurt people, vs succeed and save people. It would be relatively easy to calculate the risk/benefit objectively.
That's also an ideal use case for prediction markets, if you want to get really good predictions.
Also, I've heard this argument used before in other contexts. Do people really believe that because you can't make perfect predictions, you should default to inaction? That's just silly. You do the best with what you know and believe.
And if you really believe your predictions are wrong, then you can just adjust them accordingly and make them correct. If you don't believe that, then you obviously wouldn't find that argument convincing in the first place.
I'm not sure how this is even controversial. We should try to save the most people possible. It doesn't matter who is responsible for a death, it's just as sad whether it's cancer or a failed drug.
Any rational person would take a one in a billion risk of dying in a medical trial if it gave them access to all sorts of cures and treatments for terrible diseases. And that's if we were selecting participants at random from the entire first world population, when it's actually done by consenting volunteers who get paid for the risk they take.
It does matter who is responsible for a death. In the same way we don't pick people off the street and harvest their organs, so long as there are 2+ people on the donor pool who could use them.
To follow that:
1. People aren't rational.
2. You're not talking about "Roll this dice and we'll cure all manner of things." You're talking about "Roll this dice and we maybe, if everything goes well and it shows efficacy, might see a treatment for a disease on the market in a few decades".
3. It's not 1 in a billion. It's 1 in X, where X is unknown. Asking a volunteer to take that risk is both easier and more ethical if you've done your best to minimize X.
>In the same way we don't pick people off the street and harvest their organs, so long as there are 2+ people on the donor pool who could use them.
Well ideally we should do that. If it really saved more people. It could be done entirely voluntarily, through a lottery. And it would be rational for everyone to sign up, since you are more likely to need an organ at some point in your life, then to lose the lottery.
The rest of your comment is just a misunderstanding of statistics. Out of decades of hundreds of phase 1 trials, very very few people have died. The risk is known. We also have invented many new drugs that have had many benefits and saved many lives, which can also be measured.
I have a PhD in Epidemiology. Studying risk is what I do for a living. And no, the risk is not known. It's known to be "pretty damned low" for the aggregation of all Phase I trials, but for any given patient, and any given drug, we don't know the risk.
Approaching clinical trials in human subjects with caution and care is what has made that risk as low as it is.
That's just not how probability works at all. You absolutely can put a number on risk. You can look at past drugs like it that and determine what percent caused harm in humans after passing animal trials. You can narrow it down to drugs that are similar.
If you want to get really advanced, which isn't necessary, you could fit a bayesian model to all the data you have. Or use a prediction market to determine the risk.
Don't confuse uncertainty with unpredictable. Everything is uncertain, but few things are unpredictable.
As all of these drugs are novel, the best you can do with "similar drugs" is to come up with a decent prior for a Bayesian risk model. But since each of these drugs is new and untested then no, you don't have a numerical risk. You cannot say "1 in 167,234" or "1 in 1 Billion". You can say "Likely to be very, very small", but if you can conjure the risk of side effects for a drug with no data ever generated on that drug, I'd be impressed.
For the sake of argument, say there have been 100 drugs tested in the past. One of them killed someone, the rest were completely harmless.
Now the next drug comes along to be tested and you know absolutely nothing about it. You need to estimate the risk, and all you know is the information above. Of course your estimate must be 1%. Unless you have more information to update that probability, 1% is the optimal baseline prior.
You seem to be confused about what probability is. It's just a representation of uncertainty.
There is no such thing as "actual probability"! An event either happens 100% probability, or doesn't happen with 100% probability. There is nothing else. If you flip a coin, it doesn't have 50% probability of landing heads. The atoms and their path through the air is predictable, and it is already determined that it will land heads by the time it's left your thumb, and perhaps long before.
But you don't know that, so you can only estimate 50%. All probability is just a representation of your own uncertainty.
If you bet anything other than 1% risk, over time you will lose money. After thousands of trials, 1% of them will go bad.
>> "I'm really surprised that this is news[...] Apparently deaths during trials are really rare."
That's why it's news. If it was a regular accepted occurrence it wouldn't be news. At the start of the Syrian civil war deaths and battles were front page news, now they happen daily and we don't hear about it.
I don't think he is drawing the connection you see there. I read it like you the first time.
I think he meant that he is surprised it is newsworthy and is also surprised at how rare they are. He was assuming these were more common, but not being reported on.
I remember reading a paper on this topic many years ago (sorry I can't find it now), but the participants were at higher risk getting to the trial site than anything that happened during the trial.
You know the best way to "do no harm"? Do nothing. If you accept that doing nothing is, in fact, doing harm, then the comment you're replying to has a good point.
Or vaccines, which have a guaranteed market basically forever (or at least until eradication), and are an active part of many drug company's portfolios.
It's a popular flippant statement, but it's not born out in fact.
Gilead offers a cure (well, now, two) for Hepatitis C, yet there is an uproar about the cost (US$60,000 and up).
So, they are under a lot of pressure to drop the price severely and already charge much less outside the U.S.
Now, contrast if they had made it a chronic treatment, needing dosing forever, and charged US$10K-15K/year. The media would have hardly bat an eyelash at that cost... and Gilead would have have made more money in the long run.
Making no point about whether further control/regulation is appropriate, I'm not sure I like your logic. Treating lives as some fungible resource where the ends justify the means and whatever process results in the most living people at the end shouldn't be correct.
I sympathize with all the sick people who will die, but they were mostly selected for death naturally. The man who died (or will, as soon as life support is removed) was healthy prior to this study. Much like our justice system is supposed to value not punishing the innocent over punishing the guilty, our medical system is supposed to value not hurting the well over helping the sick. The hippocratic oath embodies this "first do no harm" principle.
> Treating lives as some fungible resource where the ends justify the means and whatever process results in the most living people at the end shouldn't be correct.
To be fair, while that is generally considered the "right thing", it is reasonable to debate it. The question of "at what point does the welfare of the many outweigh the welfare of the few" is a rather complex one.
One question that I think highlights this well is...
> There's a train headed for a group of 5 people that it will kill. You can flick a switch and make it take another track. However, doing so will make it run over 1 (different) person. Do you flick the switch?
Edit: To be clear, I'm not saying I believe that the needs of the many always outweigh the needs of the few. I'm only saying it's not as cut and dry as some people seem to say it is. It's something that should sometimes be discussed based on the situation.
I don't like the train analogy in this case. You are faced with two choices: Kill five people or kill one. Medicine is never that cut and dried. "First, do no harm" is a sound moral position in the later case.
It is when you look at it in aggregate. It's an insight that I think most of the general population misses - that when you start to deal with interests of thousands or millions of people, things start to get much more mathematical.
Consider the more zoomed-out equivalent of the train analogy: your hospital has 6 dying patients; one of them requires a serious procedure, the others need less complicated care. You don't have enough resources to help all of them - you can either spend everything on the single complicated procedure and save one patient, or distribute it to save the other 5. Which do you chose?
> "First, do no harm" is a sound moral position in the later case.
But it's a black and white moral position that doctors in the real world can't cling to on anything more than a casual basis.
All treatment comes with risks, from mild side-effects all the way to death. Surgery is inherently risky, and people die all the time. Cosmetic surgeons perform surgery all the time without being struck off.
Then there's abortion, euthanasia, and refusal to treat people without medical insurance.
"first do no harm" is closing your eyes and acting as if you don't know those 5 people are going to die, because you don't want to face the risk you'll kill 1. And in terms of life-years saved, the expectation is much better than that for medicine.
If we really followed the prescription to "First, do no harm" then really we would have to stop doing surgery completely. If giving someone a drug which hasn't conclusively been proven to be safe is harm then cutting someone open certainly is. Someone may die from an unproven drug. Someone may also die from complications from surgery or anesthesia. But surgery will certainly leave a hole in their body.
> Treating lives as some fungible resource where the ends justify the means and whatever process results in the most living people at the end shouldn't be correct.
That idea, with perhaps taking QALYs or something similar into account, seems like a pretty intuitive goal to me from an ethical standpoint. What do you suggest we should be optimizing for instead?
A collection of people is not a column in a spreadsheet or inventory. The most valuable thing in the world is a human life regardless of callous examples of how cheaply they can be had or taken. Just because you can measure two different systems using a blind metric like "most living people at the end" doesn't make it ethical. Ethics apply to individuals as much, if not more so, as groups.
That doesn't help us choose what to do. A collection of people is important, and another collection of people is important, and one of these collections of people is going to die and we have to choose which one. Platitudes about the domain of ethics don't help us to choose.
That isn't the situation at all. One group of people was going to die regardless. Or was going to suffer a life-long disease. The debate is whether or not killing people that weren't going to die is worth it if your body count is lower at the end. We're not debating whether or not flipping the switch on a train track is ethical.
We are not worth anything except to each other—value is dative, if you will. The importance of human life is no less true just because it’s subjective to humans.
If the target of medicine would be to maximize the amount of living humans, it's most effective method would be forced impregnation. If the target was to minimize the amount of deaths, then the optimal way to achieve it would be to sterilize everyone. It is clear that the solution has to be more nuanced than that.
Medicine should not exist to modify the body count of mankind. It's aim has to be realted to improving quality of life.
> Treating lives as some fungible resource where the ends justify the means and whatever process results in the most living people at the end shouldn't be correct.
This is a fundamental problem in ethics -- and like many such problems, there is no "right" answer. There is no reason it shouldn't be that way, and no reason it should.
Let's not beat around the bush here. The issue is whether people have the right to take these risks for themselves. No one makes you sign up for a medical trial.
But most people who sign up for medical trials are not terribly well informed of how dangerous the drug is. They are also usually from the poorest part of society (except terminally sick people hoping the latest trial may bring a cure.)
Actually, I don't much like this attitude. The company offers between 100 and 4500 euro to participate in trials (max earnings 4500 per year), though I don't know what they offered for this particular trial.
We can wonder why people sign up for this when the only recompense offered is [a small amount of] money but its likely due to a desire for money, caused by a lack of it -- we can only suppose that if these folk had enough money already then they wouldn't have signed up to this. It would be interesting to see the demographics of the participants of drug trials like these and I'm guessing that excess wealth and ennui aren't significant features there.
Its always worth keeping in mind that choices which may seem to be unpalatable to you are likely to be much less so to other people for reasons they don't necessarily have any control over.
So because they're poor, they shouldn't be allowed to make their own decisions? Honestly, the philosophy would be more equitable if we just extended this thinking to the whole population, right? Let's ban drinking, ice-climbing, skydiving, smoking, sweet cars, and burgers, just to get started. Because we know better than them.
The risks are understood for medical trials. Maybe they're not acceptable to me, but they are to someone else. Who am I to tell another man what risks he can take with his own life?
> So because they're poor, they shouldn't be allowed to make their own decisions?
I'd phrase it differently. Because they're poor, a certain level of financial incentive to participate in a dangerous activity may fundamentally become coercion.
You're pulling a rhetorical trick with the definition of the word "coercion". Coercion usually means forcing someone to do something without giving them the option to be left alone. That kind of coercion is widely agreed to be bad, so the term "coercion" has a strong negative connotation. Paying test subjects to take experimental drugs is not coercion in that sense, and it's not widely agreed to be bad. You're trying to make it sound bad by expanding the definition of coercion to cover it, but you haven't provided a justification for why this kind of "coercion" should be considered bad--except that it kind of resembles "coercion" in the usual sense.
Unfortunately, this kind of rhetorical trick is pretty effective. My options for responding are to either argue with you about what the word "coercion" means (which is a meaningless argument) or to claim that "some kinds of coercion are OK" (which sounds really bad taken out of context). But even though it's an effective argument, it doesn't contribute to the conversation; people who already agree with you will think it sounds convincing, but people who don't agree won't be convinced. Would you consider elaborating on your argument by explaining why you think that paying patients to participate in drug trials has the same negative features as "coercion" in the usual sense?
Anything else would be extremely unethical, not to mention completely irresponsible. Communism was and is a flawed ideology in making sure we had food to eat - what kind of monster would suggest we use capitalism to give us everything else, except what will save peoples lives? How many people have to be murdered waiting on a transplant list when we know that allowing the sale of organs means they don't have to wait (https://en.wikipedia.org/wiki/Kidney_trade_in_Iran)?
Treating lives as some fungible resource where the ends justify the means and whatever process results in the most living people at the end shouldn't be correct
Ultimately, this is an issue of individualism vs totalitarianism. Once you let go of the (western) idealist view that every individual should have full freedom of choice on how to direct their own life, a whole host of different approaches to life and state are available to you.
I like the link you made between the judicial presumption of innocence and the Hippocratic oath. It's given me a new perspective to entertain.
100% agree, and I'd add the fact the there are not enough trials for drugs that instead of curing illness do thing like slowing aging or improving mental performance or otherwise improving physical or mental performance for healthy people, simply because most people are retarded enough to think that it's not ok to risk lives for purposes like "improving IQ by 10%" or "increasing lifespan by 10%".
We should absolutely make drug trials easier and cheaper to do, and also make it easier to test drugs that seek to do other things than fixing illnesses. Not freak out because of some accidents and add even more regulation. And yeah, we probably need more regulation, but for things like production, use and sales (like state-imposed price ceilings would come to mind for drugs). But we definitely want LESS regulations for research and testing! Despite tragic incidents like this one.
My bad. I've read about this from a different source, not the linked article, and it omitted this piece of information. I've deleted my last line comment concerning this, but it doesn't affect what I was trying to say, which was more in relation to the parent comment than to OP's linked article anyway.
Your argument misses one crucial issue: what is the probability that a drug at this stage of testing will A) work and B) be safe such that it becomes a valid standard of care treatment?
If the probability is really low, then less caution will result in cases like these outcompeting the incremental benefit to humanity.
I'll give you a hint. The probability is really low.
we will never notice the deaths that happen because we were too timid or cautious in our approach
Garbage. We already know about the death toll from disease, because that's what motivates us to develop drugs in the first place. We are in fact well aware of the opportunity cost, and the notion of opportunity cost is fundamental in economics, and the people who work at regulatory agencies are in fact quite familiar with the the cost:benefit ratios involved.
You know, one of the really irritating things about libertarians is their habit f going about restating basic truisms of economics as if they're some great new discovery. Your approach has already been tried and found wanting. Every time I hear this argument I think of all the people I saw with horrific deformities growing up because their mothers were prescribed Thalidomide during pregnancy. Your economic argument falls apart as soon as you start accounting for externalities instead of waving them away as the price of progress.
Seeing this reminds me of how there is never an exciting story to publish for the far greater of number who suffer great illness or death because of regulators being too cautious about allowing trials of new treatments.
This is why for years here on Hacker News I have been more than a little skeptical about university press releases announcing that this or that group of researchers has discovered a new breakthrough for curing this or that human disease. It is wonderful that medical researchers continue to do basic research better to understand physiology, genetics, and biochemistry. And it is especially wonderful that researchers doing basic research sometimes think about translational research to apply to basic science findings to clinical medicine. But that takes a lot of time and careful work.
Here on Hacker News, we all like to be excited by possible breakthroughs that will help us or our loved ones to enjoy longer, healthier lives. But an announcement of a laboratory result in cultured cell lines or in mice or some other preliminary model is a LONG way from a demonstration of safety and effectiveness for a new treatment of a human disease. Let's keep funding and celebrating basic research, and let's keep advancing the frontier in clinical trials on human patients, but let's reality-check every step of the way to make sure that proposed new treatments really do good, and really do more good than harm.
For perspective on this, it's important to note that age-adjusted all-cause mortality has been steadily going DOWN all over the world. Life expectancy at age 40, at age 60, and at even higher ages is still rising throughout both the developed countries and the still developing countries of the world.[1] Right now, the number-one thing we can do to reduce our own risk of disability or death is to take action on known individual preventive measures that raise likelihood of good health and to set up institutional incentives for doctors and other practitioners to use best-practice means of preventing and treating disease. Steady incremental improvements of many kinds are increasing healthy human lifespan all over the world at all ages.[2]
[1] "The Biodemography of Human Ageing" by James Vaupel
I think your perspective is exactly right. Most of the articles you see on HN are about pre-clinical work (not done in humans). This is so early in the development time that the chance of the technology failing is huge.
Keep in mind that for drugs that actually enter human trials, the success rate is typically less than 5%.
One of the recommendations from the previous episode (TGN1412) was that in the first trial on humans, the administrations should be staggered so that if there is an unexpected adverse reaction, you only get one or two patients down. It sounds like that may not have been taken on board.
The six men received the drug several times, starting on Jan. 7.
The first symptoms appeared in one man on Sunday;
he was quickly hospitalized, and the other men followed.
The trial was halted the next day.
They began receiving the drug on January 7, but no symptoms of a problem appeared until this past Sunday.
The drug in question is a Monoclonal Antibody (mab) intended to boost immune response. [1] Mabs do have a tendency to runaway reactions. [2].
Mab treatments are likely to explode in coming years as immunomodulators to both boost the immune system to fight disease and suppress immune reactions in autoimmune diseases (some arthritis, asthma, severe allergies, etc)
You have to dig to find this information, posting it here for visibility.
And of course, the information around this particular drug is completely missing or intentionally vague. edit: there seems to be a lot of people who believe the drug is a FAAH2 inhibitor, based on previous work from the same company, Bial Pharmaceuticals out of Portugal. The drug works on/around endocannabinoids, which might be why the media was confused about this being cannibis related.
I believe the drug you reference is discussed as a previous case in which people were injured during clinical trials. The current casualties are part of a test of a different investigational cannabinoid pain-killer.
Replying as I can no longer update: I misread the article. I would follow this post [1] by Derek Lowe for more accurate info. If preliminary reports are correct the drug in question may be a FAAH inhibitor [2] which could lead to increased Andandamide [3]
Contrary to several reports in the French news media, the drug was not a cannabis-based painkiller, Ms. Touraine said.
Early reports in The Guardian, the BBC, and elsewhere called it a cannabinoid-based painkiller. (That sounded rather implausible because (a) cannabinoids have a ridiculously high therapeutic index -- ratio of medically effective dose to toxic dose -- and (b) with cannabis decriminalization spreading internationally, the commercial benefit of patenting a drug in the same space as a cheap non-proprietary alternative would appear to be small.)
Edit: The Guardian amended their piece to state that it was a monoclonal antibody targeting the brain's endocannabinoid receptors. (Interesting idea, but Mabs have some really lethal failure modes, notably triggering a cytokine storm in some cases, cf. TGN1412.)
cannabinoids have a ridiculously high therapeutic index
Some cannabinoids have a high therapeutic index. Some of the THC analogues being used as "fake weed" are quite toxic.
Also, there is a huge market for cannabinoid-like drugs. If you have chronic pain, would you want to be stoned all day? Or take a drug that provides pain relief, but doesn't alter your mood?
You don't test Phase 1 anticancer drugs in healthy volunteers. So likewise monoclonal antibodies for Parkinson's should probably be first tested in the affected population.
Because we need to know about drug side effects, and it's extremely difficult, if not impossible, to parse out those effects in people who are already very sick. Additionally, those side effects are likely far less dangerous in an otherwise healthy individual.
Only when they're known to be toxic, drugs which are considered otherwise benign (or at least not excessively toxic) which include some newer cancer drugs are tested in healthy volunteers.
So it might be an FAAH inhibitor?
one quick google search later
So one of the things that FAAHs do is handle "endocannabinoids", which are chemicals that activate cannabinoid receptors, which are (as the name implies) also triggered by cannabis. That'd explain why people thought it was a cannabis-based painkiller.
Can someone smart (I am not it) explain how can something that you ingest orally create brain damage? What is an example of something simpler that we all may be familiar with that could cause a similar effect, and the process through which it happens?
It simply get absorbed in the gut (like food or all medicines), into the blood. There is a 'blood-brain barrier' that many things cannot cross, but far from all.
Painkillers, caffine, LSD, and other psychoactive drugs all cross this barrier by definition. In terms of damage, there are many possible mechanisms once in the actual brain tissue. Quite often drugs would act on a receptor on a cell, which would change how the cell operates in some way, such as by inhibiting an ion channel.
Layman translation: Methanol is transformed into Formate, that is another substance. Formate mess with the functions of the mitochondria, that are the parts of the cells that use the oxygen. So each cell dies like it would die if you can't breath oxygen.
(I suppose that the neurons are more sensible, and the visual problems are easier to spot, so one of the first symptoms of Methanol poisoning is blindness.)
increased blood pressure leading to a stroke
localised inflammation of brain tissue (which can be caused by an autoimmune response)
oxygen deprivation
enzyme degradation, where an external chemical blocks some of the chemical processes that keep brain cells working (drinking mercury will do this)
The second one seems to have happened here. The may have drug triggered a wildly excessive autoimmune response called a cytokine storm, which is the immune system's equivalent of a firework display where everything is launched at the same time. This basically poisons you from the inside in various colourful and unpleasant ways.
There's nothing about oral ingestion that makes it more or less likely to cause brain damage. Many chemicals can survive stomach acid and pass into the blood stream. The drug on trial was one of them.
The majority of people reading this sentence have the JC virus present in their brains right now. Medications that suppress the immune system's ability to keep the JC virus in check can lead to PML, a brain-destroying disease that's often fatal. One oral medication that has led to cases of PML is dimethyl fumarate, marketed as Tecfidera.
Just some background about clinical trials that may yield more insight into the drug approval process:
Phase I: intended to determine a loose range of safe doses for patients. Subjects enrolled in Phase I clinical trials are informed that it is unlikely for the drug to benefit them. Normally, subjects are healthy volunteers that are put into buckets of different doses to determine the Maximal Tolerated Dose (MTD).
Phase II: Intended to characterize the efficacy of the drug (on a small scale). There are several methods of conducting Phase II trials; some are simply longitudinal case studies, and others are structured more like randomized controlled trials (the type of clinical trial generally considered the most valid [i.e. maintains the highest internal validity]).
Phase III: Randomized controlled trial. Patients are randomized into the test group vs. placebo/current standard of care to determine whether the new drug is effective. The best RCTs are double-blinded though this is not always the case.
This drug, a monoclonal antibody intended to alter the immune response, was halted in the Phase I clinical trial.
Are all Phase 1 trials done on healthy human guinea pigs. Why do we allow otherwise healthy people to be guinea pigs? Presumably there are patients who have the disease this drug targets.
Parkinson's is a toughie - you don't really know what a patient is suffering from, just the syndrome they're exhibiting. I "have Parkinson's", by which I mean I have a series of symptoms that aren't related to any known purely-genetic disease (there are several, and I've been tested for all of them), tumors or structural issues in the brain (lived many a night in various scanning devices), are similar in general tone to those common to Parkinson's sufferers, and which respond well to treatments for Parkinson's. The syndrome itself, though, is a bit idiosyncratic, and may in fact be a constellation of similar diseases rather than a single disease. Diagnosis is still mostly a process of observation and elimination, despite what a few optimistic studies may have reported.
Phase 1 is typically done to determine dosing and side effects. It's more difficult to get this information from unhealthy subjects - more confounding factors.
While this is truly a sad event, there are some things to note here, primarily:
This was a Stage 1 trial, whose sole goal is to determine the minimum-tolerate dose. The idea here is that after we've identified a possible drug, we do preliminary tests in animals and follow some well established dosage-scaling formulas to determine human dosages.
They then scale that waayy down, and gradually scale up the drug in different patients until side-effects are noticed.
Although the article describes the patients as being healthy, people who volunteer for these types of studies usually have exhausted all possible alternatives and aren't usually given good prognosis.
If a study is conducted ethically, they aren't given any hope that the drug will positively effect them in any way, and that they are truly doing this for the possible benefit of Stage >1 patients.
Usually, toxicity is found before patients die (although that happens). What makes this unprecedented, imho, is that so many died. What makes it personally disheartening is that one is brain-dead, which is a special kind of hell for a family to go through.
While these patients weren't told "this drug will murder you, or maybe leave you brain-dead, with high-likelihood", however, in a Phase I trial, that is very much the risk you're running at such an early stage of drug development.
people who volunteer for these types of studies usually have exhausted all possible alternatives and aren't usually given good prognosis.
According to other comments here (e.g. https://news.ycombinator.com/item?id=10910698), this is incorrect. Stage 1 is given to otherwise healthy patients, to ascertain adverse effects of the drug. Stage 2 is where the positive effects of the drug are tested, that seems like the case you're describing here.
You are correct, and I beleive I mentioned in my comment that the sole purpose of Stage I is to asses the minimal tolerated dosage.
What I meant by the sentence you quoted is that because of the unknown human physiological consequences of the drug, it is usually only used on those who have no other recourse. Patients that have a clear course of treatment undergo those clear courses, and do not assume the risk of a Phase I drug.
I can't seem to find the name of nature of the drug in question, does anyone know it? I ask because full CB1 agonists are already known to be problematic, but none of the articles mention anything other than endocannabinoid
When it is the first use in humans, and the main point of Phase 1 is safety, why is there not an exponential turn on of the trial to avoid widespread harm? For example Patient 1 gets medicine for a week (or whatever), then patients 2 & 3 start their trial, etc. Where is the economic analysis of length of test vs risk of harm by various turn on strategies?
It's a series of filters - you test on animals before testing on humans. Of course some percentage of things that are not toxic to animals have a special toxicity in humans. To claim that it is "useless" means that you also believe there to be a large proportion of candidates which are toxic in animals that aren't toxic in humans.
I don't have the data on this, but, without necessarily defending the practice of animal testing, I suspect that toxicity in animals is a good predictor for toxicity in humans in the forward direction.
185 comments
[ 5.1 ms ] story [ 229 ms ] threadReading the FDA recall database is quite illuminating
http://www.fda.gov/Drugs/DrugSafety/DrugRecalls/default.htm
The food one is also an eye opener, 8 so far in 2016
http://www.fda.gov/Food/RecallsOutbreaksEmergencies/Recalls/...
Last year I scraped the whole database and read every one to analyse the reasons for a Uni project. I'm surprised anyone is still alive!
This is France we're talking about here, we are one of the most regulated country on the planet, this includes FDA like institutions. Still, this could happen anywhere. Also, as has been pointed elsewhere, too much regulation can make people die that could have benefited from the a cure, except we don't notice these death.
But yeah, striking the balance between progress and safety is tough. It's just sort of comforting to see a tragedy minimized by the controls we've put in place.
This seems like a bit of an issue.
EDIT: Not the same trial, I'm a fool.
There is a duty of care and caution needed in medicine. Of course this needs to be balanced with the damage from slowing or preventing innovation.
Somehow, "move fast and break things" doesn't quite translate to biology.
While this case should be studied to ascertain whether process changes could prevent it, the solution is absolutely not further testing, control, and regulation. Hundreds of thousands of people already die or suffer every year because of the paternalistic, conservative policies governing medicine.
But there's a difference between minor tweaks to address the root causes of this issue (hypothetical: maybe the drug got contaminated in transit and post-shipping verification of contents needs to be done) and a "Shut it down, shut it all down" reaction.
To draw a thin (but perhaps appropriate analogy): after the hijackings of airplanes on September 11th, the United States responded by expanding the air marshall program, significantly jacking up security and restrictions on passengers, and putting combination locks on airplane cabins. Only the last policy, I think, is actually necessary to address what happened on September 11th, and it's all they should have done.
https://www.schneier.com/blog/archives/2010/04/the_effective...
It just lets him claim he 'did something', and makes the base democratic voters happy.
All of those things which we require of drivers should be required of those who operate guns.
In America, there's this confounding problem of that Amendment. To change anything, that's got to change too.
We need to fix our violence problem, nobody disagrees about this. But it seems like many Democrats, like Obama, are convinced the only right way to do that is making it more difficult for gun owners to buy guns.
Rather than say, targeting actual problems with a clearly defined link to the crime: Many school shooters steal guns from family members. If Obama actually wanted to reduce shootings, he'd look into how to solve that, rather than pursuing a party agenda instead.
No, just expanding it. It has existed since the 60s.
Where do you draw the line?
PS: Prescription drugs already make some top ten killers lists in the US, there far less safe than generally assumed.
So, misuse by someone is very high, but hard to pin down.
One way of comparing these numbers is to look at changes in life expectancy. But that changes very slowly suggesting minimal change per year from one years new drugs. Actual deaths from prescription drugs are also hard to measure, but generally assumed at well over 20,000 per year. http://www.voxeu.org/article/genuine-innovation-new-drugs-sa...
Call it ~6-12 months lost vs. ~1-2 months gained. Though the clear upside is those gains should stack year over year. Just not when you compare introducing drugs a few months early as they would have made it to the market anyway.
PS: The clear conflict of interest is the fairly short lifespan of drug patents.
What you have presented is evidence that net of deaths from drugs, each year's new drugs offer an extra 2 months of life expectancy to those living in developed countries. By inference, a new regime which uniformly imposed a six month delay to drug development would cost a net 1 month of life expectancy per person. Across a population the size of the US, that's over 300 million months of human life expectancy, or an order of magnitude more whole human lives than your figure for all prescription drug deaths...
It's true approving nothing would cost more lives, but that does not mean defaulting to accepting everything is a good idea either. After-all, Opiates are not known as a life saving drug, even if they prevent a lot of pain.
Thus, the 20k+ or ~1% of all deaths are part of the accepted costs for our current system. Don't forget there are plenty of drugs that are not associated with any deaths.
If someone is alive, are they alive because of the drugs? How could that even be quantified?
My statement is that on average X(n) is clearly well under 20,000. So, plenty of caution is warranted.
And that's just one disease.
Medical research is conservative, cautious, and regulated because we strive to move beyond the ugly abuses of our past[2]. It should not be the Wild West.
For insight into modern medical ethics, read the Belmont Report[3]. It's what contemporary researchers must read before conducting any studies involving human subjects. Where I work, we're tested on it.
(This is opinion, but...) Harm today is in research guided more by profit than by benefit. Chronic disease is more profitable than cures or prevention. With rapidly-emergent antibiotic resistance there is little private incentive to develop new antibiotics. We must rely on and expand research in the public interest (funded by NIH, philanthropy, and so on) to balance private biomedical research.
1. https://en.wikipedia.org/wiki/Primum_non_nocere
2. https://en.wikipedia.org/wiki/List_of_medical_ethics_cases
3. http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html
As kauffj eludes to though, it's also worth considering the implicit harm done through inaction. It should not be the wild west, but conversely, articles like this are indicative of a bias toward increasing prevention of active, explicit harm at the expense of more unseen, implicit harm through inaction.
As with anything, there's a happy medium.
A lot of the value of "First, do no harm" comes from the point that we have a bias toward action over inaction. Humans, including doctors, want the ability to control our futures. So the temptation is constantly to do something instead of saying "well, that sucks, but we don't have strong reason to believe anything we do will substantially improve things." That's why we perform way too many interventions (particularly, invasive and surgical ones) that at best marginally improve average outcomes at incredible cost and substantial risk. Doctor and patient both want a magic fix. And all too often the fix is more harmful than helpful to the individual patient, even if on average it might be slightly beneficial.
Obviously there's a place for heroic surgical efforts and research into exotic drugs. But we over invest in those compared to the alternatives of prevention and palliation. Conservatism is useful in medicine.
Mainly, I think it's worthwhile to point out what appears to be dogma on both sides of any debate.
That is, patient outcome is better for patients who go to a hospital with a good reputation, that has outstanding doctors (a teaching hospital) -- but the outcome is best when the top doctors are NOT present in the hospital when the patient checks in.
After controlling for many variables, the only explanation the authors of the study came up with to explain this apparent paradox, is that top doctors want to try anything, esp. the latest procedure/drug, while non-top doctors are more conservative.
At least in the short term, being conservative saves lives.
1. https://hms.harvard.edu/news/startling-benefit-cardiology-me...
Imagine you want to be appear more muscular. You could get implants under general anesthesia or you could take steroids. The first is legal, but the second is illegal. It is illegal because society deems that taking steroids is excessively risky. However general anesthesia and surgery are orders of magnitude more dangerous.
This same bias present throughout medicine. Many surgical procedures and tests would never pass the FDA's requirements for pharmaceuticals.
Casting this as a ridiculous argument completely ignores the viewpoint that there may well be externalities caused by this behavior that don't necessarily affect the individual but do affect other individuals. If we take as an example the consumption of illegal drugs the argument can be made that it should be the choice of the individual and not restricted by society, however there is a potential for significant costs (due to the behavior of the individual when under the influence of the drug) that are placed onto the society, thus the subsequent restrictions placed on the individuals.
To be clear I am not intending to debate drug policy or be an apologist for the current war on drugs. My point is to illustrate that a perspective that considers the externalities of a behavior is not a ridiculous position to take as you assert.
[1] https://news.ycombinator.com/item?id=3819346
Are you suggesting we've made "no real progress in the field" of medicine since 1910?
>A meta-analysis of non-cancer Phase 1 drug trials, published last year in The British Medical Journal, found serious adverse events in only 0.31 percent of participants, and no life-threatening events or deaths.
And the last event comparable to this, according to the article, happened in 2006 in a different country.
I was surprised by this. I would not have expected drug trials to be risk free, in fact I thought that was the whole point. Apparently they are already super conservative and safe. I'm not sure why people are alarmed or calling for more regulation.
It's probably impossible to 100% safety, and certainly not desirable. Parent comment is definitely right that we kill more people through inaction and need to be far more liberal. Total lives saved is all that should matter.
Somehow one person dying out of many drug trials over many years is news that's on the front page of HN. But the 22,000 people that died of cancer today isn't.
Medical ethics are expressly meant to protect subjects from experimentation purely on the basis of "This will probably help more people than it hurts." Given the events that prompted the development of those guidelines, I'm not sure they're wrong.
And why is this bad?
Interesting, do you have any actual examples of this?
That's also an ideal use case for prediction markets, if you want to get really good predictions.
Also, I've heard this argument used before in other contexts. Do people really believe that because you can't make perfect predictions, you should default to inaction? That's just silly. You do the best with what you know and believe.
And if you really believe your predictions are wrong, then you can just adjust them accordingly and make them correct. If you don't believe that, then you obviously wouldn't find that argument convincing in the first place.
Any rational person would take a one in a billion risk of dying in a medical trial if it gave them access to all sorts of cures and treatments for terrible diseases. And that's if we were selecting participants at random from the entire first world population, when it's actually done by consenting volunteers who get paid for the risk they take.
To follow that:
1. People aren't rational. 2. You're not talking about "Roll this dice and we'll cure all manner of things." You're talking about "Roll this dice and we maybe, if everything goes well and it shows efficacy, might see a treatment for a disease on the market in a few decades". 3. It's not 1 in a billion. It's 1 in X, where X is unknown. Asking a volunteer to take that risk is both easier and more ethical if you've done your best to minimize X.
Well ideally we should do that. If it really saved more people. It could be done entirely voluntarily, through a lottery. And it would be rational for everyone to sign up, since you are more likely to need an organ at some point in your life, then to lose the lottery.
The rest of your comment is just a misunderstanding of statistics. Out of decades of hundreds of phase 1 trials, very very few people have died. The risk is known. We also have invented many new drugs that have had many benefits and saved many lives, which can also be measured.
Approaching clinical trials in human subjects with caution and care is what has made that risk as low as it is.
If you want to get really advanced, which isn't necessary, you could fit a bayesian model to all the data you have. Or use a prediction market to determine the risk.
Don't confuse uncertainty with unpredictable. Everything is uncertain, but few things are unpredictable.
Now the next drug comes along to be tested and you know absolutely nothing about it. You need to estimate the risk, and all you know is the information above. Of course your estimate must be 1%. Unless you have more information to update that probability, 1% is the optimal baseline prior.
You seem to be confused about what probability is. It's just a representation of uncertainty.
It's not the actual probability of an adverse side effect.
But you don't know that, so you can only estimate 50%. All probability is just a representation of your own uncertainty.
If you bet anything other than 1% risk, over time you will lose money. After thousands of trials, 1% of them will go bad.
That's why it's news. If it was a regular accepted occurrence it wouldn't be news. At the start of the Syrian civil war deaths and battles were front page news, now they happen daily and we don't hear about it.
I think he meant that he is surprised it is newsworthy and is also surprised at how rare they are. He was assuming these were more common, but not being reported on.
http://www.alltrials.net/news/comment-from-ben-goldacre-on-t...
A ridiculous comment. What about the latest cure for HCV? It's been vastly more profitable for the company than any chronic treatment.
It's a popular flippant statement, but it's not born out in fact.
Gilead offers a cure (well, now, two) for Hepatitis C, yet there is an uproar about the cost (US$60,000 and up).
So, they are under a lot of pressure to drop the price severely and already charge much less outside the U.S.
Now, contrast if they had made it a chronic treatment, needing dosing forever, and charged US$10K-15K/year. The media would have hardly bat an eyelash at that cost... and Gilead would have have made more money in the long run.
I sympathize with all the sick people who will die, but they were mostly selected for death naturally. The man who died (or will, as soon as life support is removed) was healthy prior to this study. Much like our justice system is supposed to value not punishing the innocent over punishing the guilty, our medical system is supposed to value not hurting the well over helping the sick. The hippocratic oath embodies this "first do no harm" principle.
To be fair, while that is generally considered the "right thing", it is reasonable to debate it. The question of "at what point does the welfare of the many outweigh the welfare of the few" is a rather complex one.
One question that I think highlights this well is...
> There's a train headed for a group of 5 people that it will kill. You can flick a switch and make it take another track. However, doing so will make it run over 1 (different) person. Do you flick the switch?
Edit: To be clear, I'm not saying I believe that the needs of the many always outweigh the needs of the few. I'm only saying it's not as cut and dry as some people seem to say it is. It's something that should sometimes be discussed based on the situation.
Consider the more zoomed-out equivalent of the train analogy: your hospital has 6 dying patients; one of them requires a serious procedure, the others need less complicated care. You don't have enough resources to help all of them - you can either spend everything on the single complicated procedure and save one patient, or distribute it to save the other 5. Which do you chose?
Now scale that up to the country-level.
This feels like an incomplete argument to me.
> "First, do no harm" is a sound moral position in the later case.
But it's a black and white moral position that doctors in the real world can't cling to on anything more than a casual basis.
All treatment comes with risks, from mild side-effects all the way to death. Surgery is inherently risky, and people die all the time. Cosmetic surgeons perform surgery all the time without being struck off.
Then there's abortion, euthanasia, and refusal to treat people without medical insurance.
That idea, with perhaps taking QALYs or something similar into account, seems like a pretty intuitive goal to me from an ethical standpoint. What do you suggest we should be optimizing for instead?
You also have to preserve human rights, for example. You could argue that trialing a potentially deadly drug took away a basic one from these people.
Until I hear that from a sentient creature that is not human, I won't accept it as an universal truth.
Medicine should not exist to modify the body count of mankind. It's aim has to be realted to improving quality of life.
This is a fundamental problem in ethics -- and like many such problems, there is no "right" answer. There is no reason it shouldn't be that way, and no reason it should.
We can wonder why people sign up for this when the only recompense offered is [a small amount of] money but its likely due to a desire for money, caused by a lack of it -- we can only suppose that if these folk had enough money already then they wouldn't have signed up to this. It would be interesting to see the demographics of the participants of drug trials like these and I'm guessing that excess wealth and ennui aren't significant features there.
Its always worth keeping in mind that choices which may seem to be unpalatable to you are likely to be much less so to other people for reasons they don't necessarily have any control over.
The risks are understood for medical trials. Maybe they're not acceptable to me, but they are to someone else. Who am I to tell another man what risks he can take with his own life?
I'd phrase it differently. Because they're poor, a certain level of financial incentive to participate in a dangerous activity may fundamentally become coercion.
Unfortunately, this kind of rhetorical trick is pretty effective. My options for responding are to either argue with you about what the word "coercion" means (which is a meaningless argument) or to claim that "some kinds of coercion are OK" (which sounds really bad taken out of context). But even though it's an effective argument, it doesn't contribute to the conversation; people who already agree with you will think it sounds convincing, but people who don't agree won't be convinced. Would you consider elaborating on your argument by explaining why you think that paying patients to participate in drug trials has the same negative features as "coercion" in the usual sense?
Ultimately, this is an issue of individualism vs totalitarianism. Once you let go of the (western) idealist view that every individual should have full freedom of choice on how to direct their own life, a whole host of different approaches to life and state are available to you.
I like the link you made between the judicial presumption of innocence and the Hippocratic oath. It's given me a new perspective to entertain.
We should absolutely make drug trials easier and cheaper to do, and also make it easier to test drugs that seek to do other things than fixing illnesses. Not freak out because of some accidents and add even more regulation. And yeah, we probably need more regulation, but for things like production, use and sales (like state-imposed price ceilings would come to mind for drugs). But we definitely want LESS regulations for research and testing! Despite tragic incidents like this one.
The way things are, it's good to be careful.
If the probability is really low, then less caution will result in cases like these outcompeting the incremental benefit to humanity.
I'll give you a hint. The probability is really low.
Garbage. We already know about the death toll from disease, because that's what motivates us to develop drugs in the first place. We are in fact well aware of the opportunity cost, and the notion of opportunity cost is fundamental in economics, and the people who work at regulatory agencies are in fact quite familiar with the the cost:benefit ratios involved.
You know, one of the really irritating things about libertarians is their habit f going about restating basic truisms of economics as if they're some great new discovery. Your approach has already been tried and found wanting. Every time I hear this argument I think of all the people I saw with horrific deformities growing up because their mothers were prescribed Thalidomide during pregnancy. Your economic argument falls apart as soon as you start accounting for externalities instead of waving them away as the price of progress.
Here on Hacker News, we all like to be excited by possible breakthroughs that will help us or our loved ones to enjoy longer, healthier lives. But an announcement of a laboratory result in cultured cell lines or in mice or some other preliminary model is a LONG way from a demonstration of safety and effectiveness for a new treatment of a human disease. Let's keep funding and celebrating basic research, and let's keep advancing the frontier in clinical trials on human patients, but let's reality-check every step of the way to make sure that proposed new treatments really do good, and really do more good than harm.
For perspective on this, it's important to note that age-adjusted all-cause mortality has been steadily going DOWN all over the world. Life expectancy at age 40, at age 60, and at even higher ages is still rising throughout both the developed countries and the still developing countries of the world.[1] Right now, the number-one thing we can do to reduce our own risk of disability or death is to take action on known individual preventive measures that raise likelihood of good health and to set up institutional incentives for doctors and other practitioners to use best-practice means of preventing and treating disease. Steady incremental improvements of many kinds are increasing healthy human lifespan all over the world at all ages.[2]
[1] "The Biodemography of Human Ageing" by James Vaupel
http://www.demographic-challenge.com/files/downloads/2eb51e2...
[2] http://www.slate.com/articles/health_and_science/science_of_...
Keep in mind that for drugs that actually enter human trials, the success rate is typically less than 5%.
(1) It sounds like the trial started on July 9
(2) These 6 people all started receiving the drug January 7 and all got sick
(3) 90 people total have received the drug, so I assume 84 people safely received the drug.
This sounds like there was a bad batch that hospitalized everyone who received the drug on January 7.
Mab treatments are likely to explode in coming years as immunomodulators to both boost the immune system to fight disease and suppress immune reactions in autoimmune diseases (some arthritis, asthma, severe allergies, etc)
You have to dig to find this information, posting it here for visibility.
1. https://en.wikipedia.org/wiki/TGN1412
2. http://www.ncbi.nlm.nih.gov/pubmed/20305665
And of course, the information around this particular drug is completely missing or intentionally vague. edit: there seems to be a lot of people who believe the drug is a FAAH2 inhibitor, based on previous work from the same company, Bial Pharmaceuticals out of Portugal. The drug works on/around endocannabinoids, which might be why the media was confused about this being cannibis related.
She was also very careful to insist that the drug neither contains cannabis or any substance derived from cannabis.
1. http://blogs.sciencemag.org/pipeline/archives/2016/01/15/a-c...
2. https://en.wikipedia.org/wiki/Fatty_acid_amide_hydrolase
3. https://en.wikipedia.org/wiki/Anandamide
Contrary to several reports in the French news media, the drug was not a cannabis-based painkiller, Ms. Touraine said.
Early reports in The Guardian, the BBC, and elsewhere called it a cannabinoid-based painkiller. (That sounded rather implausible because (a) cannabinoids have a ridiculously high therapeutic index -- ratio of medically effective dose to toxic dose -- and (b) with cannabis decriminalization spreading internationally, the commercial benefit of patenting a drug in the same space as a cheap non-proprietary alternative would appear to be small.)
Edit: The Guardian amended their piece to state that it was a monoclonal antibody targeting the brain's endocannabinoid receptors. (Interesting idea, but Mabs have some really lethal failure modes, notably triggering a cytokine storm in some cases, cf. TGN1412.)
Some cannabinoids have a high therapeutic index. Some of the THC analogues being used as "fake weed" are quite toxic.
Also, there is a huge market for cannabinoid-like drugs. If you have chronic pain, would you want to be stoned all day? Or take a drug that provides pain relief, but doesn't alter your mood?
https://en.wikipedia.org/wiki/Phases_of_clinical_research#Ph...
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678815/
[citation needed]
It would be strange in English, to my eyes, to refer to a newspaper whose name was "The World" as theworld.
It is sometimes referred as "lemonde.fr", but the space is never omitted if we are not citing the web domain (with its TLD).
So one of the things that FAAHs do is handle "endocannabinoids", which are chemicals that activate cannabinoid receptors, which are (as the name implies) also triggered by cannabis. That'd explain why people thought it was a cannabis-based painkiller.
In advance, thank you for educating me.
Painkillers, caffine, LSD, and other psychoactive drugs all cross this barrier by definition. In terms of damage, there are many possible mechanisms once in the actual brain tissue. Quite often drugs would act on a receptor on a cell, which would change how the cell operates in some way, such as by inhibiting an ion channel.
https://en.wikipedia.org/wiki/Neurotoxin
Layman translation: Methanol is transformed into Formate, that is another substance. Formate mess with the functions of the mitochondria, that are the parts of the cells that use the oxygen. So each cell dies like it would die if you can't breath oxygen.
(I suppose that the neurons are more sensible, and the visual problems are easier to spot, so one of the first symptoms of Methanol poisoning is blindness.)
increased blood pressure leading to a stroke localised inflammation of brain tissue (which can be caused by an autoimmune response) oxygen deprivation enzyme degradation, where an external chemical blocks some of the chemical processes that keep brain cells working (drinking mercury will do this)
The second one seems to have happened here. The may have drug triggered a wildly excessive autoimmune response called a cytokine storm, which is the immune system's equivalent of a firework display where everything is launched at the same time. This basically poisons you from the inside in various colourful and unpleasant ways.
There's nothing about oral ingestion that makes it more or less likely to cause brain damage. Many chemicals can survive stomach acid and pass into the blood stream. The drug on trial was one of them.
Phase I: intended to determine a loose range of safe doses for patients. Subjects enrolled in Phase I clinical trials are informed that it is unlikely for the drug to benefit them. Normally, subjects are healthy volunteers that are put into buckets of different doses to determine the Maximal Tolerated Dose (MTD).
Phase II: Intended to characterize the efficacy of the drug (on a small scale). There are several methods of conducting Phase II trials; some are simply longitudinal case studies, and others are structured more like randomized controlled trials (the type of clinical trial generally considered the most valid [i.e. maintains the highest internal validity]).
Phase III: Randomized controlled trial. Patients are randomized into the test group vs. placebo/current standard of care to determine whether the new drug is effective. The best RCTs are double-blinded though this is not always the case.
This drug, a monoclonal antibody intended to alter the immune response, was halted in the Phase I clinical trial.
This was a Stage 1 trial, whose sole goal is to determine the minimum-tolerate dose. The idea here is that after we've identified a possible drug, we do preliminary tests in animals and follow some well established dosage-scaling formulas to determine human dosages.
They then scale that waayy down, and gradually scale up the drug in different patients until side-effects are noticed.
Although the article describes the patients as being healthy, people who volunteer for these types of studies usually have exhausted all possible alternatives and aren't usually given good prognosis.
If a study is conducted ethically, they aren't given any hope that the drug will positively effect them in any way, and that they are truly doing this for the possible benefit of Stage >1 patients.
Usually, toxicity is found before patients die (although that happens). What makes this unprecedented, imho, is that so many died. What makes it personally disheartening is that one is brain-dead, which is a special kind of hell for a family to go through.
While these patients weren't told "this drug will murder you, or maybe leave you brain-dead, with high-likelihood", however, in a Phase I trial, that is very much the risk you're running at such an early stage of drug development.
No one died from this trial.
According to other comments here (e.g. https://news.ycombinator.com/item?id=10910698), this is incorrect. Stage 1 is given to otherwise healthy patients, to ascertain adverse effects of the drug. Stage 2 is where the positive effects of the drug are tested, that seems like the case you're describing here.
What I meant by the sentence you quoted is that because of the unknown human physiological consequences of the drug, it is usually only used on those who have no other recourse. Patients that have a clear course of treatment undergo those clear courses, and do not assume the risk of a Phase I drug.
testing an animals beside being a cruel practice that has to be stopped, is also useless even when the animals are that close to humans.
I don't have the data on this, but, without necessarily defending the practice of animal testing, I suspect that toxicity in animals is a good predictor for toxicity in humans in the forward direction.