French drug trial leaves six hospitalized, one brain-dead
nytimes.com
nytimes.com
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.
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.
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.
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...
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?
(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.
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.
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.
Reading 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.
https://en.wikipedia.org/wiki/Phases_of_clinical_research#Ph...
[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).
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%.
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.
This seems like a bit of an issue.
EDIT: Not the same trial, I'm a fool.
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.
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.
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.
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.
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.