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Experts Decry Randomized Ebola Treatment Trials As Unethical, Impractical
New submitter Strangely Familiar writes "A letter in the Lancet calls for alternatives to randomized trials for Ebola treatments: "Leading health experts today urge the deployment of alternative trial designs to fast-track the evaluation of new Ebola treatments. In a letter to The Lancet, 17 senior health professionals and medical ethicists, from Africa, Europe, and USA, argue that although randomised controlled trials (RCTs) provide robust evidence in most circumstances, the lack of effective treatment options for Ebola, high mortality with the current standard of care, and the paucity of effective health care systems in the affected regions means that alternative trial designs need to be considered."
One of the biggest threats our civilization faces - is our hellbent political correctness at any cost.
If you don't understand what I mean by that, I'll try to explain: Here in Scandinavia, socialism is on the rise, everyone has the right to everything and the news increasingly censors any opinion that would be against socialism or popular accepted opinions. We have to look human to the entire world at any cost, so if one of us would contract Ebola outside Scandinavia - the politically correct thing to do would be to bring home our own citizens to treat them in our own country instead of isolating it and treating them where it happened.
I see the same thing happening in other socialist dominated countries. Ebola is DEADLY and it's on the rise way faster than we originally anticipated, doctors that have sufficient protection has been infected.
Why did we do experiments on mice, rats and monkeys? Why do we do experiments on volunteering humans? We do this for the good of everyone, political correctness will do you very little good if your future prospects is death, and possibly an outbreak where you live. Where do you run then?
Politics / hear-say and Science doesn't mix. We've got to listen to our scientist and facts rather than depend on touchy-feely feelings and PC.
What this world is coming to - is for you and me to decide.
If they are serious they really need to get more big names, institutions, and ethicists on board. A lot more.
There has already been support for basically using time to create control groups, so this is much less of an issue than it could be.
Seriously, starting to experiment with uncertain approaches in a time of crisis is about the most stupid thing that can be done. Stick to what is known to work, there is no time to come up with anything better. If something better had been found in centuries of research into medical methods, then it would be the standard-approach. There is nothing. There will not be anything new even if you debate that question to death now.
This continues the series of incompetence, misinformation, self-aggrandizement and general fuck-ups that have become the signature of the fight against Ebola this time.
Most ACs are not even worth the keystrokes to insult them. Be generically insulted by this and ignored otherwise.
I understand their concern, but ZMapp hasn't even passed stage 1 clinical trials. We don't know if it's safe for humans or not. It could kill more people than it helps. Having randomized trials is how we establish the safety level of the drug.
It may be useful to 'fastrack' the drug through stage 2 trials, since by that point we know it won't kill you.
"First they came for the slanderers and i said nothing."
I dunno who Beecher is, but the real beginnings of the "placebo effect" idea were in the 1800s when people started realizing that doing nothing was better than whatever the doctors said to do (bloodletting, etc).
argue that although randomised controlled trials (RCTs) provide robust evidence in most circumstances, the lack of effective treatment options for Ebola, high mortality with the current standard of care, and the paucity of effective health care systems in the affected regions means that alternative trial designs need to be considered."
Translation:
Even though randomized trials are the gold standard for determining whether a treatment is effective or not, these places have shitty health care systems so we think should do something else now that we know is a bad idea even though it will be detrimental in the long run rather than engage in the hard work that will really solve the problem.
Conveniently these "alternative trial designs" are not detailed in any way. Doing something different for the sake of doing something different is rarely a good idea.
We use randomized trials for VERY good reasons. If we push a bunch of experimental treatments out there it's possible we may save some lives but it is more likely we will accomplish nothing and even worse we will learn nothing in the process. Yes some people are going to die from ebola while we develop treatments. This is the cold hard fact of medicine - we sacrifice some so that a greater number may benefit eventually. You can try taking shortcuts but the odds are very long against them working and even worse you run a high risk of sacrificing future patients on the altar of compassion.
I get that people are dying and my heart goes out to them. But we do things the way we do them for very good reasons and the middle of a (minor overblown) crisis is hardly the time to start throwing out what we know for a fact works.
The placebo effect is well-established and real. It is well established that it continues to work with smaller effectiveness even when the subjects _know_ they are getting placebos. Stop bringing some new-age bullshit into the discussion, it is not helping. Medical statistics (unlike medicine as often practiced) is a very mature field and delivers reliable results.
Most ACs are not even worth the keystrokes to insult them. Be generically insulted by this and ignored otherwise.
> the politically correct thing to do would be to bring home our own citizens to treat them in our own country instead of isolating it and treating them where it happened.
> I see the same thing happening in other socialist dominated countries.
Er, it happened in America too and you couldn't exactly describe them as socialist.
But randomized trials were designed to be used in a certain set of circumstances. The question is whether these circumstances fall outside of what those would be applicable to and what would be the appropriate protocol if they're not. Being too rigid can be a bad thing but also things should not be done in a knee-jerk fashion.
Randomized trials worked just fine for syphilis.
The available ZMapp was wasted in a worthless political demonstration "that something can be done".
Quote so. There were only a few doses available and without a trial of statistically significant size we cannot possible know if this treatment was effective. Ebola is serious but it doesn't kill everyone it infects. So if you give a treatment to a tiny group of people you have absolutely no way to know if the treatment was effective. You have wasted time and money and hope and learned absolutely nothing in the process. It's idiotic.
The signatories to that letter in Lancet are willing to shoulder any monetary and/or criminal penalties that, in the future, come about because doctors and pharmaceutical makers haven't followed eatablished best practices in pursuit of effective Ebola treatments.
#DeleteChrome
Using history as a guide (Polio, AIDS) their first attempts will kill/maim a bunch of people with no benefit. The public will clamor, so the best we can hope is the vaccine is harmless.
"Medical statistics (unlike medicine as often practiced) is a very mature field and delivers reliable results."
What evidence do you have for this? In fact, the stats they use were made up on accident by EF Lindquist (guy who created the ACT) when he got confused while writing an introductory textbook for teachers. So a priori we should doubt they are reliable.
Er, well how about use non-treated people as the control group? If the placebo effect is a few percent and the disease kills 70% then it really doesn't matter. If the effect of a drug is so small that it's masked by the placebo effect then the drug is worthless: 65% or so are still going to die of the disease. A worthwhile drug[0] would reduce mortality by at least half, ideally 90%, which is simply not going to be masked by a placebo effect.
[0] I'm not saying that the lives saved by a drug that reduced mortality by 5% wouldn't be worth saving, just that if a drug had such a small effect it would be better investing in more research to find a better drug rather than in mass producing the 5% improvement drug.
Any more meaningless generalities to contribute? The field is not static or rigid. The problem is just that generating and validating new drug-trial methods takes decades and cannot really be sped-up. The whole reason we have this gold-standard of randomized trials is that all else has failed. The worst was always the physician on the ground deciding about it, as they have a strong, well-known (and understandable) tendency to always favor their own patients and an inability to clearly see what is happening as a result. That is fine as it is, of course doctors should be strong allies to their patients and try whatever is possible if the patient wants that. It is also catastrophic when objective information about effectiveness or its absence of some treatment is critically needed. All this messing around that these people propose will in the end only cause more victims, potentially a lot more.
Most ACs are not even worth the keystrokes to insult them. Be generically insulted by this and ignored otherwise.
Seriously, THAT DOES NOT WORK. This idea is for armchair-statisticians only. You NEED the same conditions for the control-group or the results are meaningless.
Well, that is not entirely true. With a medically very well-monitored population where in addition all contacts of everyone are closely monitored and well documented, something might be possible to do with advanced, untested, statistics. I hope you can see that not even western societies meet that requirement by a far cry.
Most ACs are not even worth the keystrokes to insult them. Be generically insulted by this and ignored otherwise.
If passengers are lying about having contact with Ebola infected people . . . they will just pop a couple of aspirin to bring down their temperature before landing.
Very un-PC, but it will help them avoid yet even more delays while trying to catch a connecting flight.
Schroedinger's Brexit: The UK is both in and out of the EU at the same time!
drive-by doctoring is Unethical, Impractical but legal and you are on the hook for the fees some at out of network rates.
Indeed. And if you kill that bunch of people without sound conditions to get a statistical handle of what happens, you just make things worse by wasting time.
A lot of emergency medicine is still in its infancy and is risky, bloody and deadly. Done wrong, it becomes a lot more so. Get used to it.
Most ACs are not even worth the keystrokes to insult them. Be generically insulted by this and ignored otherwise.
Nothing will ever convince conspiracy theorists, so I am not even going to try.
Most ACs are not even worth the keystrokes to insult them. Be generically insulted by this and ignored otherwise.
What conspiracy? Fisher came up with significance testing, Neyman and Pearson came up with hypothesis testing, the two sides feuded and then Lindquist created the nonsense hybrid they use today.
http://www.ncbi.nlm.nih.gov/pubmed/17286092
Although I disagree on the emphasis you place on "statistics", I agree that we can't really rule out anything if they use unblinded, unrandomized trials. My issue is that even in that case a RCT isn't very good evidence on the basis of statistical significance alone. You need independent trials showing similar effect size to be convincing. Disproving that death rates were exactly the same between two groups is pointless due to baseline differences, etc. Blinding eliminates alot of bias, randomization (loosely) minimizes the size of a random effect we would expect, but still other explanations for an effect need to be ruled out.
Isolate is the MAIN tool to get rid of this menace. So why would the health organizations insist on bringing them to other countries? SO that they can "help isolate" the organism on their behalf...come up with a very expensive cure. Very profitable if it escapes esp. A sad state of affairs when people are so greedy to "help themselves" to others perils. And what happens if some of these researchers morphs it into a real easily transmitted strain of Ebola? Hey Africa is the next BIG thing afterall..
WHO is already looking at stepped wedge trials
Let's say you had an alternative statistical method for judging treatments during a crisis situation like Ebola. It's not out of the question. All sorts of statistical methods have been developed for situations where you can't get the number and type of observations you want. Now think about applying that method where the Ebola crisis is happening. You think the data collection is going to be any better than the health care? It's going to be worse. I spent ten years working with data from emergency rooms in the U.S. It's got lots of problems. Of course it does, the doctors are more concerned about healing the patients than they are about collecting data. Which is the way things should be. You think the doctors in Africa dealing with Ebola right now have the time or training to deal with the data collection?
The point of randomised controlled trials is to form a perfect control group for comparison.
More or less correct. You are trying to control for variables between the treated groups and the non-treated groups to see if there is a statistically significant difference in outcomes between them. If there is a better way to do this than a double-blind study, we haven't found it yet. We do use other study designs when a double-blind study isn't possible but other methods have significant problems.
So why not start giving the drug to everyone and compare against historical data?
Several reasons:
1) Which drug? Do we have enough of it? Can we get it to where it is needed? Has it been previously tested in humans for toxicity? Is there any reason to believe it will work beyond mere hope?
2) We do NOT have particularly good information in the historical record. The medical records in the affected areas are quite certain to be of poor quality. So you lose a LOT of information that is relevant for making comparisons and you do not have a particularly good control group.
3) Unless you can control for other variables like public health policies etc you may not know if it worked or how well.
4) Rushing a drug to market can result in losing valuable information about WHY it worked (or didn't) which may be more valuable than IF it worked to future patients
5) Most drugs do not work. Do you REALLY want to spread already scarce resources even thinner on a long shot that probably will not work?
They may do something like what you suggest but I think that would be a mistake. We KNOW how to control this virus through public health policy. Hyperventilating and throwing a bunch of unproven drugs at the problem in the (probably futile) hope that they will do some good is not only bad policy, it is probably counterproductive.
If the patients in question fully understand that they might not be getting treatment, and they're totally OK with not being treated, whats the problem? Obviously, they may have a hard time getting volunteers, but at the same time, I would hope the patients realize that they aren't getting treated right now anyways with much more than replacement fluids, and have the same odds as a coin toss whether they live or die. So what do the patients have to lose?
As for the article... if you're going to basically bum-rush ebola with some wacky experimental drug, be prepared for something like what happened with Thalidomide, or much worse. They very well may end more lives than they save by doing something like that. Cliche, I know, but the road to hell is paved with good intentions.
Lastly, if they have some brilliant replacement for the scientific method, me and the rest of the world would probably like to know. Pretty sure they don't, so this is just basically the timeless griping about how unfair the world is.
they're simply desperate to find anything that will stop it.
We already know what we stop the epidemic. Appropriately executed public health policies, particularly quarantine. I understand people's fear and desperation but public health policy is not the place for panic. To use a basketball analogy these people are proposing taking half-court shots and hoping for the best rather than doing the hard work of actually doing what we already know will work. We are NOT going to save everyone but rushing things along is very likely to actually kill more people in the long run.
Even if a treatment gives them cancer, or HIV, or leaves them with something like chronic fatigue syndrome, they're still going to enjoy quality of life better than they would if they're dead.
What hypothetical treatment do you think will have this outcome? Hmm? What treatment? Very few drug candidates actually prove effective and there is no reason to believe that things will be any different this time. I'm well aware there is work being done regarding this disease but please share with the class what treatment we expect to have any actual hope of working because I certainly am not aware of it.
If there's any time to drop stages between reasoned research and application on human patients, this is it. Look at each and every patient as they're treated and attempt to monitor them after-the-fact.
I could not disagree more. First off, this is a small epidemic that has gotten blown WAY out of proportion in the media. Second, there is absolutely no reason to expect any particular experimental drug to work. While it is possible one might work, the odds are very long against it. Third, this approach actually hinders our ability to learn about WHY a drug works if by some miracle it actually does work. Fourth, ebola is not universally fatal. Between 20%-50% of patients survive. Unless the effects of a drug are VERY dramatic, you'll never know if the drug is what saved a patient.
Yup. The problem with treating zmapp as a cure without evidence is that it might turn out that it doesn't work at all, and that other research lines were not pursued because zmapp was viewed as a cure. Why might this happen? Well, for starters there actually isn't THAT much money to be made in a cure for Ebola. I don't agree with the tinfoil hat types that anybody would deliberately not develop a cure, because the fact is that a cure would generate a reasonable profit if not a huge one. However, the world probably doesn't need 47 different cures for Ebola and the first one to the market is likely to get 95% market share. If companies perceive that zmapp is basically on the verge of being labeled as the cure, then they're not going to spend a lot of money on another cure just to fight for the scraps.
And you can't really be sure without a control. There are all kinds of bias, perverse incentives, and other factors that can lead to misleading data in the absence of a true double-blind controlled trial. Doctors often falsify data in clinical trials because of perverse incentives. Companies do it less often since they're more closely monitored and falsifying data at that level often requires conspiracy, but they obviously have a huge incentive to do it if they could get away with it. A double-blind trial helps to keep everybody honest.
If passengers are lying about having contact with Ebola infected people . . . they will just pop a couple of aspirin to bring down their temperature before landing.
If they are showing symptoms, a high temperature will not be the only symptom in evidence most likely. Aspirin is VERY unlikely to cover the symptoms of ebola. Plus taking a blood thinner (aspirin) when infected with a disease that results in bleeding is a monumentally stupid idea.
I can't believe protocols for pandemic control don't already exist! H1N1 should have prompted governments to discuss the process for testing new fast-tracked medical practices in a reliable manner while minimising spread and maximising delivery. Within each simulation, a shortage of delivery should be predicted. Methodologies for overcoming these shortages such as emergency grants of patent licences with subsidies covering production cost should already be in place. I guess it could be argued that we haven't truly hit pandemic scale in regions with the resources to implement such plans. Of course, its not a true pandemic until Madagascar closes its borders ;)
Instead of randomizing with placebo, why not simply randomize with _different_ experimental treatments and then use analysis / datamining to determine which are most effective? That way no one has to have placebo.
Actually I would suggest that the problem is worse than that. Coming up with a good or even brilliant idea in a crisis is not implausible; it has been done many times in the past. Some people actually perform best under pressure.
However here is the problem. Suppose we decide to come up with a 'good sounding idea', and of course we all want to help disadvantaged people whose lives are under threat. What if our good sounding idea turns out to be wrong? We could wind up applying ineffective treatments. We could unwittingly block the search for better care. We could actually kill patients who would otherwise not have died.
Now consider that west Africa is a lesser developed area of the world with a history of colonialism. Anything we do that is sloppy, or too quick, or fails in any way will be judged by the people there. And here, for that matter. If we rush drug testing (or indeed just skip that step completely) then we will be accused of the sins of the past: rascism, colonialism, paternalism, the rich not caring about the poor, etc.
There is a reason that double blind clinical trials are the gold standard of pharmaceutical testing. All other methods have proven to be worse. Even double blind trials can fail or mislead, but they do so at lower rates than other methods.
So go ahead, skip the best scientific methods that we have. Just don't be surprised if it blows up in your face and all your good intentions are then interpreted as bad intentions. Your reputation will be ruined and you will be accused of killing defenceless sick people. Is that what you want your legacy to be?
Seriously, starting to experiment with uncertain approaches in a time of crisis is about the most stupid thing that can be done. Stick to what is known to work, there is no time to come up with anything better.
It's not a question of experimentation with uncertain approaches. The alternatives are all well-understood... actually the mathematics is straightforward enough that the characteristics of virtually any approach you can invent can easily be calculated.
The question is whether they should use the approach that provides the fastest route to a given level of certainty at the expense of deliberately leaving a significant percentage of sufferers untreated, or whether to use other methods that provide the treatment to everyone possible but will take longer to achieve the required level of certainty. There's a legitimate question here, particularly if the researchers strongly believe that the vaccine does work. In that case, using randomized treatment will needlessly allow many people -- and, in particular, healthcare workers -- to die. If, on the other hand, the vaccine really isn't very effective, then delaying the discovery of that fact, and therefore delaying evaluation of alternative vaccines (assuming they exist) will cost more lives.
In any case, this isn't a question of experimenting with uncertain approaches. The pros and cons of all of the options are fully understood. It's just a question of deciding which set of tradeoffs is the best for this situation.
Note to ACs: I usually delete AC replies without reading them. If you want to talk to me, log in.
It's not ethical to administer treatment until we have reason to believe it's more likely to do good than harm. With top of the line supportive care, ebola patients seem to have about even odds to pull through. Giving them something toxic or using limited money on unproven medication rather than access to good supportive care could well jeopardize those odds. Initial trials should be done on just big enough groups to establish necessary statistical confidence.
Now if side effects are few and financing is not at the expense of proven medicine, it's a different story. But too often, ethics is violated for experimental cancer drugs. People are given toxic drugs that increase suffering without solid evidence that they will increase remaining quality or even quantity of life.
I'm amazed of how you lot managed to completely split my OP totally apart, and take it totally out of context and bring in just about any irrelevance you could possibly bring to the table. After reading all of your replies, I tried hard to decipher what could have triggered what I wrote into the obvious troll thread it became and what angered you lot so much that you ended up with the answers you wrote. Maybe I had a moment of "pure idiotic", or I inadvertently stirred up so many emotions in you that you just simply couldn't stay on topic. Let's summarize:
- One contributor attacks me for using the word Censored (which is me misspelling the word Censure) and thus derails the topic.
- It gets better, another contributor thinks that 13% of our population are idiots.
- And then another contributor somewhat thinks it's important to point out that he thinks I must be a far-right Nazi sympathizer or something.
- AAAAND numerous contributors can't for the life of them connect communism to socialism which leads to Censorship, so therefor I'm obviously so illiterate that I didn't make that connection either.
- And if I disagree with all of the above, then I'm one of those tin-foil hatters (obviously) that believe that the would should end yesterday and no matter what they say, I'll still be stuck in yesteryear.
Ok, let's get this topic back ON TOPIC shall we? I'll try one last time before I simply wave my white flag, climb down my prepper bunker and hide until the world according to Urkel returns to the day when my father was a little girl:
We - the people have a tendency to let our feelings get in the way of science. Sure, ethics is what set us apart from the animals...even I will buy that one, but what I was trying to say here was that we need to let science be science and keep ourselves to the facts instead of letting our feelings run away with the better of us.
The Ebola virus MUST be isolated BEFORE it reaches too many countries and gets totally out of hand. The only way to do this is to treat the virus where the virus is, instead of bringing the infected people home and thus risk the entire population. I can't understand why that could be so hard to understand, explain it instead of dumping a gazillion personal attacks.
In communistic regimes - censorship is pretty common and it's very hard to get any unbiased communication across anywhere. But it isn't just communist countries that tries hard to put a damper on communication, socialist countries isn't far away either, Sweden is an excellent example of this (and this is something that a LOT of Swedish people think too, just ask them or read some of the few unbiased uncensored forums & newspapers there are).
When science gets ignored, say...basic cleanliness and routine becomes extinct. Let me take Denmark as an example. In Denmark it's considered very rude not to help out when you're invited to Dinner, everyone wants to chip in. That's the nice part, what wasn't so nice though was that it's very common that the visitors often go directly to chopping up vegetables and handling meat without even bothering to clean their hands. This issue became so big in Denmark that it made headlines in the news, people where simply so social that it was considered fanatic to be too clean and it made you look unsocial if you where to remind others of their basic hygiene.
Now, if you can't see the connection here, maybe I simply suck at explaining it to you, but I can pretty much promise you - these things are really related.
What this world is coming to - is for you and me to decide.
Seriously, starting to experiment with uncertain approaches in a time of crisis is about the most stupid thing that can be done.
But that is "doing something"! Haven't you heard of the First Rule of Bad Decision Making yet?
1. "We must do something!"
2. "Here is something."
3. "Let's do it!"
During a "crisis", doing nothing or doing things the same way you do normally (for whatever reason), is a mortal sin in the eyes of many PHB types.
Oliver.
The Placebo Effect is known to have at least one huge flaw in its theory. There have been several experiments involving Placebo Opiates and Placebo Opiate Antagonists in double blind studies with real drugs of both kinds, and the researchers doing them have pretty much disproved that the Placebo Effect works in any of the ways theories say it might.
In fact, one prominent researcher said of these studies, he was now of the opiniion that it was not possible to phrase whatever was really happening in a natural language, and he could not offer a theory that fit all the facts without it sounding like "Four-sided, colorless, green triangles meditate furiously. Other researchers have simply pointed out that, in their tests, the explanations of what should be expected in using placebo opiates simply don't have any pedictive ability when the tests also mix in treating those addicted patients with possible placebo antagonists, and left it at that.
Who is John Cabal?
Randomized trials are essential withholding potential treatment from some suffering patients, to satisfy some of the experimenters' goals.
So why not allow the experimental product to be administered outside of the trial, having only passed safety standards? That can provide solid evidence for a large category of illnesses (those that people are not known to recover from spontaneously).
Then, if some folks want more rigorous evidence of efficacy, they are welcome to find patients who accept to participate in the randomized trials. Maybe by compensating them in some way for the risk they are taking? (It's possible that nobody would accept such a deal, so what?)
Or maybe by modifying the protocol so that they get the treatment for sure if their condition worsens?
These comments are mine; I do not speak for my employer.
You NEED the same conditions for the control-group or the results are meaningless.
No you don't. There are only two states you need to worry about, i.e. dead and not dead. We already know the death rate of untreated Ebola, so you can use that as a control group.
And you can't really be sure without a control.
Is the fact that there are less dead people in the zmapp group vs the current untreated death rate not enough of a control for you? You people don't know shit about how medical studies work, there are only two outcomes with this virus, and that is dead vs not dead. It would be very easy to derive the P value of the zmapp treated group relative to the known death rate of the virus.
http://www.cnn.com/2014/09/27/...
Assuming this is honest, it seems amazing. Mortality rate down to 13%. When you're talking epidemic, throwing everything against the wall to see what sticks seems like the only way to do it. You think they have problems getting people to go to the hospital now, imagine how hard it would be if word went around that you might wind up in a control group?
There is nothing stopping us from conducting double blind randomized trials with animals, why has everyone overlooked this fact? You can even do concurrent studies, in the human group you can do a step wedge trial and in the animal group you can do a randomized trial.
I do not claim that doing the statistics right gives you perfect data. Far from it. But If you do the statistics wrong, you are ensured to get bad data and that potentially kills a lot of people with the problem at hand. So doing the statistics right is an ethical imperative, even if the results are only so-so.
Most ACs are not even worth the keystrokes to insult them. Be generically insulted by this and ignored otherwise.
Indeed. With the current situation, the delay would be lethal for a lot of people.
And antivirals have been duds before after being heralded as miracle cures. Just think of Tamiflu, for example. Last I heard it had "no effect".
Most ACs are not even worth the keystrokes to insult them. Be generically insulted by this and ignored otherwise.
Really, it is not "for me" where the problem sits. It is for those sick and dying and all those that will get infected in the future. Learn a bit about statistics maybe? And while dead/not dead may be a reasonable approximation for Ebola, it is not for ZMapp, unless you assume zero side-effects. Also, the death-rate is _not_ known, there are just some estimates and in addition it seems to be strongly dependent on factors like medical care. Or in short: The clueless one here is you.
Most ACs are not even worth the keystrokes to insult them. Be generically insulted by this and ignored otherwise.
I completely agree. There have been significant discoveries under great pressure. There have been a lot more utter disasters when experimenting under great pressure. Of course, history tends to remember the heroes, and to forget the catastrophes, but realistically, the making things worse is a lot more likely, especially when we have something we know works to a reasonable degree and when we know beyond any doubt that the problem is very, very hard.
Most ACs are not even worth the keystrokes to insult them. Be generically insulted by this and ignored otherwise.
No, you cannot "easily calculate" the mathematics of an alternate approach. In a clinical trial, you _create_ the experimental conditions and that is the only reason that you know them and can do calculations. Sure, if you have all data, then modeling is easy. You will not even get reasonable approximations in the situation at hand. Remember that hospitals refuse treatment to sick and dying people because they are full? Remember that people there bury their dead themselves? Remember that conditions are bad enough that likely quite a few people die that would have survived with reasonable care? You are _not_ going to get any useful numbers unless you control the experimental situation. And you make a second mistake: Even in completely controlled clinical trials, you have to estimate uncertainty before you can do any modeling. That requires intuition and experience. This nos mostly not a mathematical problem.
Most ACs are not even worth the keystrokes to insult them. Be generically insulted by this and ignored otherwise.
Indeed. Unfortunately, if this goes seriously wrong, it is not just one incompetent tribe that gets wiped out this time.
Most ACs are not even worth the keystrokes to insult them. Be generically insulted by this and ignored otherwise.
Studies without control group that use a placebo will prove nothing about a treatment, but are they unethical? Will it be ethical to give a placebo to someone suffering a deadly sickness?
I have a friend that worked at the Stanford medical center's pediatric intensive care unit, where his patients were often flown in/helicoptered from all over the state. There are certain diseases that have a 100% mortality rate in children, where they could be fine two weeks before, and near death when he gets them. He developed a cure that saves about half the kids, and attributes most of the lost ones for not getting then to him fast enough. Everywhere else in the world they die. Stanford, being a research hospital, allowed him to experiment. He had a dilemma that bothered him immensely-- In order to gain wider acceptance, the medical community wanted to have a double blind test to see if the test, and show statistics.. When I last spoke with him, he was thinking about the minimum set of kids that would have to die and still be statistically acceptable. This was about 8 years ago, and don't know the current status. I'm not a doctor, and may have some of the details wrong. He did mention that his point of view was controversial, and it's hard for other doctors to reconcile that his patients lived though was was normally consider a death sentence.. He mentioned that he had to manage multiple organ failure trying to restore them to health. If a child was flown in fast enough, there was a good chance of a 100% recovery.
He had an interesting theory about the body and death (if I recall correctly) -- He believes that under some conditions, the autoimmune response goes out of control and starts actively trying to kill you. A lot of disease vectors and allergies can trigger this. . He said your body actively produces a lot of nasty toxins that cause multiple organ failures.. He did research on dialysis filters, and made sure to continuously purge the blood stream for the toxins. He would also follow up with chemotherapy to aid in autoimmune response suppression.. His method called for a very high volume of IV fluid which was pretty expensive. Stanford was willing to fit the bill. He believes that this method could be used to treat older patients as well.
Through a fog of memory, I'd like find out how this guy is doing. He's still doing pediatric critical care work, but moved on to Samaritan Hospital. He tells me that a lot of doctors he knows can't handle children dying in intensive care wards. He's an optimist and thinks about the number of children he's saved.. There are unsung heroes all around us.
In this case, one of the most dangerous things you can do is partially apply a cure. Allowing people who have already been treated to remain in close contact with those still infected and resulting in re-infection is the surest way to develop treatment resistance in the targeted infectious agent. Stockpiles of any successful treatment must first be built up in countries not yet infected so that any appearance of the infection can be rapidly treated. Once those stockpiles are built upon, stockpiles to be deployed in already infected regions can be built up so that an entire quarantined region can be treated in order to significantly reduce the risk of reinfection.
Peace meal application of a treatment will guarantee the spread of the infection globally and the build up of resistance due to reinfection. The greater the spread and infection the far greater the risk of mutation into more harmful varieties.
Chaos - everything, everywhere, everywhen
Anders, is that you?
You appear to be describing antibiotic resistance. Ebola is a virus.
Confucius say, "Find worm in apple - bad. Find half a worm - worse."
There was a story some time ago, iirc it was about how paramedics were instructed to open an envelope in specific cases of emergencies, which then told some paramedics to use a specific drug for some specific procedure, and others were told not to, in order, iirc, to conduct an experiment, for establishing the usefulness of a particular drug and/or procedure. Iirc the article I read mentioned how one or more paramedics refused to hold back on treatment. Sry, don't remember the details that well.
There is something wrong with you, if you believe that it is a serious point to say "it was not possible to phrase whatever was really happening in a natural language".
Our natural languages permit the communication of arbitrarily complex concepts, as do other domain-specific forms of communication.
Four possible scenarios:
Conventional random testing, treatment's a dud.
Treatment is found ineffective, drug labs get no money, some testers die, but they would have died anyway.
Conventional random testing, treatment works.
Treatment found, drug labs get cash, some testers die that could have been prevented.
New testing, treatment's a dud.
Possible false positive, drug labs get cash, dud drug gets widely deployed giving false protection and lost of preventable deaths happen.
New testing, treatment works.
No preventable deaths occur, good drug gets widely deployed fast.
So new fast testing only makes sense if the treatment's good. But you don't know that until you test...
It also means that for those that are infected, there's so little chance of survival with "traditional" treatments that they have very little to lose by trying something experimental. Even if a treatment gives them cancer, or HIV, or leaves them with something like chronic fatigue syndrome, they're still going to enjoy quality of life better than they would if they're dead.
I would posit that the problem is not that the currently infected individual faces any fate worse than death.
The problem is that lack of high-quality data may forestall the development of more effective therapies, which means you are condemning people infected in the future to death. This latter group seems abstract and hazy, compared to the concrete suffering we can see before us, but eventually the future becomes the now, and we'll have to deal with it.
Researchers may well end up heading down blind alleys, trying to optimize ineffective strategies that end up sucking up resources (money, scientists, labs, mindshare). The history of medicine is full of useless or even harmful therapies that were developed without the benefit of rigorous clinical trials -- difficult to treat conditions like cancer were especially prone to this phenomenon (for instance, the radical mastectomy procedure for breast cancer -- painful, disfiguring and debilitating, developed during an age of heroic surgery... a "gold standard" treatment yet much much later proven to offer no survival benefit in the majority of situations).
And you can't really be sure without a control.
Is the fact that there are less dead people in the zmapp group vs the current untreated death rate not enough of a control for you?
You're talking about a zmapp group composed of people who are well fed their entire lives, of a different racial composition, and who received care in first world hospitals. Your control group is a bunch of people being given palliative care for the most part in tents and the like, most of which who probably have never been to a doctor otherwise in their entire lives.
No, that isn't a controlled experiment.
You people don't know shit about how medical studies work, there are only two outcomes with this virus, and that is dead vs not dead. It would be very easy to derive the P value of the zmapp treated group relative to the known death rate of the virus.
Anybody can load a pile of data into a statistics program and have that program output numbers. Those numbers only mean something if the data was any good. You can't do an uncontrolled experiment and get a real result out. Sure, you might use this kind of data to decide whether the expense of doing a controlled experiment is worthwhile, but on its own there are so many reasons that the results could turn out wrong they're nearly worthless.
Don't feel too bad though - lots of researchers do things just the way you describe, which is why the US spends all kinds of money on treatments that have little evidence supporting their effectiveness. While everybody likes to pick on drugs, the irony is that at least recently these tend to have quite a bit of rigor behind them. The real black magic are things like surgical treatments and the like.
Oh, and while you're doing your uncontrolled studies you should just try injecting patients with saline solution. I would expect it to have a noticeable impact on Ebola death rates - the placebo effect works on just about anything that has ever been tested.
Randomised trials, a superb cornerstone of current day medicine, works best when you are comparing different treatments, both of which sort of work, and you are trying to find out which one is better. It is currently the best way to do it.
A bit different with Ebola. About half die with the best treatments medicos have to offer. And in a country with comparatively bad health care, it is much higher. Wondering about side effects and other issues, years down the track, doesn't count for much when they are dying like flies right now.
Fast tracking treatments in this sort of scenario can be effective. If it works at all, death rates will drop by rather obvious amounts, thus paving the way for more targeted approaches. So they may die of a side effect of the treatment in 5 years? They got 5 years that they would have lost.
In a few years, ,when there is hopefully a collection of treatments that actually work, THEN it is time to do randomised trials.
LOL.
"NIH: "We May Have to Vaccinate Whole Countries to Stop Ebola Outbreak"
http://www.activistpost.com/2014/10/nih-we-may-have-to-vaccinate-whole.html?PageSpeed=noscript
That's right, the 'AIDS' fraudster 'Dr.' Anthony Fauci is trying to make millions of dollars by FORCING everybody to be 'vaccinated' against Ebola. It's just a shame that there is no such thing as 'vaccination', because Jenner was a well known fraud...
The Fraud of Vaccination:
http://www.whale.to/v/hadwen1.html
I'm still waiting for ONE person on the planet to rebut Dr. Hadwen's talks... funny how that has never been done, isn't it...
not really fair to say "well, we tried this test with 1 chem compound (opiates) and it didnt work, therefore the effect is fake"
have you seen my sig? there are many others like it but none that are the same
So how would you do an RCT for something like Ebola, a disease that really only manifests itself when it starts to spread? Would you ask for volunteers to be infected outside of an outbreak in ordered to test efficacy/safety? Is there an IRB board in the country that would authorize something like this?
I actually do agree that you don't want to get all Mavericky with drug experimentation. At a certain point though you need patients with the disease to test efficacy and safety. If the only time you have patients is during an outbreak then when else can you test in vivo responses?
-- The Genesis project? What's that?
"Disprove a strawman null hypothesis", which is the usual use of stats, is an example of "do the statistics wrong". It doesn't rule out anything so is at best a superfluous step. At worst it confuses people.
Take a look at that ZMapp paper (http://go.nature.com/oY8pGI). It was unblinded with no explanation of the "clinical score". They decided when to kill the control monkeys using secret criteria. This is clearly no evidence that the drug is effective at all, the p-values are irrelevant, and using their criteria anything can be demonstrated to be "effective". If this is typical of the quality of research going into ebola treatments please do withhold whatever they find from me.
It's time we came up with a twenty-frst century alternative to the randomized trial, like creating a supercomputer model of the human body to test drugs agaionst,
Giving half your test population of cancer patients a placebo may be merely unethical, but giving half your population of Ebola patiets a placebo could take out an entire country.
The issue of liability can be solved with consent, just as it is in the randomized trial. The number of patients to receive the treatment doesn't seem to affect liability, nor does the cost of the treatment.
Also showing product safety is generally much easier than showing effectiveness, and different people (especially those with a terminal condition) have different tolerances for risk.
The question your raise is whether you learn something from non-randomized trials (which I agree are the gold standard procedure). If there is a very lethal disease (that we're able to test for but not treat), and the people taking the treatment (in various locations, conditions, etc) fare significantly better, while the people who don't continue to die, can you draw any conclusions as to the effectiveness of the treatment? I think you can make inferences, although with lesser confidence.
The question that follows from that is, if you are a doctor or producer and have such a treatment, is it ethical or desirable for you to withhold it? That seems selfish to me (putting your preference for experiments over my preferences as a patient).
Is it ethical for prohibit the doctor or producer from delivering to consenting patients? To me, that seems paternalistic and unhelpful (not to mention of questionable political authority). It would seem much better to help inform the patients and give them support for their own choices.
As I suggested in another comment you could imagine a two prong approach: customers are allowed to get a safe but unproven product, or participate in experiments with some compensation/incentives. So you could still conduct experiments on people who accept that bundle (risk and compensation including the satisfaction of knowing they are helping science).
Whether people SHOULD participate in those experiments and therefore those experiments SHOULD continue to exist doesn't seem a categorical/universal question to me. It seems a question of preferences (demand). Assuming enough people demand the extra confidence and rigorousness, and enough people are willing to take the risk of receiving a placebo, then they will exist. Otherwise you are imposing your own will and preferences on people, which hardly seems civilized or peaceful.
These comments are mine; I do not speak for my employer.
Seriously, starting to experiment with uncertain approaches in a time of crisis is about the most stupid thing that can be done. Stick to what is known to work, there is no time to come up with anything better. If something better had been found in centuries of research into medical methods, then it would be the standard-approach. There is nothing. There will not be anything new even if you debate that question to death now.
This continues the series of incompetence, misinformation, self-aggrandizement and general fuck-ups that have become the signature of the fight against Ebola this time.
May I be polite and say that "You don't have exclusivity on intelligence". The decision to try experimental medication is a "last chance" possibility to save a life. And if it works, then perhaps it will work with others. If my life was in peril from Elboa, and I knew I had a 60% chance of dying, I would go for it.
I had a flesh eating disease(Necrotizing fasciitis) on one leg, and was told "Tomorrow we amputate, because the existing anti-biotics are not working. I responded, give me a stronger dose, and try a different medication. Result-- I still have both legs.
Yes, it is ethical, and even if it failed, we know the person would have died.
Leslie Satenstein Montreal Quebec Canada
Seriously, starting to experiment with uncertain approaches in a time of crisis is about the most stupid thing that can be done.
Not necessarily. If you have limited resources and a solution that's certain to work, then yes, it's kind of dumb to waste resources by experimenting with solutions that are unlikely to work. However, if you're having a crisis and you have no solution that's certain to work, then it may be smarter to "leave no stone unturned" and test any approach that seems like it might yield results, so long as you're pretty sure it won't make the problem worse.
If something better had been found in centuries of research into medical methods, then it would be the standard-approach.
Again, this is pretty silly. First of all, modern medicine really has only been around for a couple of hundred years. Before that, "medicine" wasn't much better than witch doctors. So when you say "centuries", it's only just barely accurate. And during those centuries, we've seen countless innovations, and we continue to see developments of better medical methods of various kinds. There's no reason to say, "Let's stop trying to innovate in medicine. If there were any room for improvement, we would have found it already."
Yeah, I'll buy that. The typical drug might have a 30% improvement in survivability vs a 20% improvement with a placebo. I suspect that when it comes to Ebola an effective treatment might have a 90% effective rate vs a 30% rate for placebo. The disease probably is lethal enough that you could be pretty sure about the results unless the treatment was only mildly effective.
Where have these "experts" been the last 25 years ?
Being open to criticism is not the same as being open to insane ramblings that ignore reality.
Most ACs are not even worth the keystrokes to insult them. Be generically insulted by this and ignored otherwise.
May I point out that this is experimentation that will result in definite action much later (due to manufacturing delays) and that it is being done in the face of something growing exponentially? Really, any risk of going in the wrong direction here will result in a couple of million more dead at the very least. That is what makes this highly unethical. Your case is not even remotely comparable.
Most ACs are not even worth the keystrokes to insult them. Be generically insulted by this and ignored otherwise.
You are the one ignorant of reality. The history of NHST was recorded in journals and textbooks. It is there for all to see, I even provided a link to a paper discussing it to start you off. You will refuse to acknowledge this because it requires a nearly unbelievable level of incompetence amongst many intelligent people. It took me about two years of looking into it (I was trained to use these methods) before I finally accepted that it is true, the way statistics have been used for the last 50 years is dangerously wrong. Ronald Fisher (inventor of the significant test) saw this situation developing and predicted mass confusion would result, he was right.
"We are quite in danger of sending highly-trained and highly intelligent young men out into the world with tables of erroneous numbers under their arms, and with a dense fog in the place where their brains ought to be. In this century, of course, they will be working on guided missiles and advising the medical profession on the control of disease, and there is no limit to the extent to which they could impede every sort of national effort."
Fisher, R N (1958). "The Nature of Probability". Centennial Review 2: 261–274.
I seenothing at all wrong with random treatments for conditions that are dire. A cancer patient who is near death, for whom all treatments have failed, has nothing to lose by trying an unreleased, not properly field tested, drug. Think about it. The doctors know that the patient will be dead in a week and have no good answers. It the new idea happens to kill the patient he simply will not suffer another awful week. On the other hand every now and then you have a "bingo" moment and the patient is helped or you learn the dose was too low or too high which helps the next patient. And even forgetting all of that it does another huge, good, thing. It gives the patient hope. People in the depths of dispair often feel like God and mankind have betrayed them, abandoned them or worse. Frankly they are right. Many times only a priest waits in the wee hours for that last awful gasp. Sometimes there is not even a priest. The medical staff sort of avoids the last hours of life as well as it frightens the staff as well. But that tiny bit of hope that the new treatment will work gives the patient some relief. Even lies can help. A patient who is in and out of consciousness can be told that he will have a new liver transplanted when he wakes up. For soem patients that is a mercyful lie that provides relief. For my two cents it makes good sense to gamble when all is almost lost. And we should have no restraints on the nature of pain killers or feel good types of dope for those who are passing even if such drugs speed up the death process. Morality and kindness do walk hand and hand.
If the vaccine is in short supply, the merits of a randomized trial seem to outweigh the ethical concerns. Regardless of the trial design there isn't enough vaccine to go around. A standard randomized trial with placebos appears to have many benefits:
- many of the difficult variables in other trial designs are controlled, leading to faster conclusions regarding the efficacy of the vaccine
- more communities can be part of the trial due to the number of injections being doubled
- if the vaccine is successful, there will be more survivors out of each community
- if the vaccine is detrimental, the entire community is not impacted
Which is worse: giving all the vaccine to one group and none to the second group, or giving some vaccine and some placebo to both groups? If we learn more from the latter, and we protect some people in both communities (thereby ensuring more healthy workers in both communities), it seems that a randomized trial is not as unethical as some would say.
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Oh, do viruses not respond to strong selection pressures then?
What in the world are thinking! Are you proposing that viruses don't mutate? Fact is, any microscopic organism can and do mutate all the time. Ever hear of influenza? HIV? Cold? Plus hundreds of other viruses?
"Those who can make you believe absurdities can make you commit atrocities." - Voltaire
Do they mutate in response to treatments against them, in a similar way to how bacteria develop resistance to antibiotics?
Confucius say, "Find worm in apple - bad. Find half a worm - worse."
Of course they do. Viruses are no different than other microbes. They will eventually do whatever it takes to propagate and survive. Which in many cases is in response to changes in their environment.
"Those who can make you believe absurdities can make you commit atrocities." - Voltaire
I never said they didn't. But do they respond to this type of treatment in the way that bacteria respond to non-fatal doses of antibiotics?
From your original post: (http://slashdot.org/comments.pl?sid=5816263&cid=48122531) "partially apply a cure" "Allowing people who have already been treated to remain in close contact with those still infected" "develop treatment resistance".
Show me a case of something akin to antibiotic resistance in bacteria, or fuck off.
Confucius say, "Find worm in apple - bad. Find half a worm - worse."