Stopping a trial early and it's statistical implications should, by the way, be somewhat familiar with web developers: it's commonly done with A/B tests, and the related problem is the "One-armed bandit" (https://en.wikipedia.org/wiki/Multi-armed_bandit#Empirical_m...)
: Legend says they are even familiar with correlation != causation, and some have mastered the advanced skill of knowing that trial size matters, which is why they started, a few years back, to test drugs on more than one person.
This is a legitimate issue in the scientific community. The FDA made it a requirement to publish drug trial criteria beforehand to prevent trials from stopping prematurely or adding more participants. This resulted in a massive drop in drugs with positive results: "...before the registry was created, more than half of the published studies of heart disease showed positive results. After the registry was created, only 8 percent had positive results". 
The FDA and scientific community isn't as "pure" as your flippant dismissal would suggest. The FDA can only do so much, and trial runners have misaligned incentives.
Considering how much money is in pharmaceuticals, I'd definitely go with corrupt, especially considering this explains how a majority of the world works now and also since there's currently an outbreak and likely want to capitalize on it.
I'm not at all saying this is the case, but that if something like that did come out then I really wouldn't br surprised considering it seems to be a weekly occurrence that you hear about corrupt behavior now.
If everyone is corrupt, then it’s OK if you are, etc.
There is no fair application of the rule of law, there’s no reason for rule of law, only the rule of men. Better hope they’re on your side!
My point is that clear corruption as we think of it (fraud, bibery, self dealing) in most Western countries is NOT considered normal. Ie. It happens but we’ve built institutions to counteract it. The FDA is notoriously bureaucratic in order to detect and prevent corruption, and for the few cases to slip through, to correct it.
When you hear about corruption stories, that’s about the system WORKING against those cynics that are testing it for their own benefit.
Cynicism is self destructive. If our institutions are broken, we must work to repair them.
Have a listen to this https://www.youtube.com/watch?v=JbIqKqojOZU
He is the author of Parliament of Whores
Parliament of Whores is an international best-selling political humor book by P. J. O'Rourke published by Atlantic Monthly Press in 1991. Subtitled "A Lone Humorist Attempts to Explain the Entire US Government"
AFAIK stopping an A/B test early is the way to go if you want to convince yourself (or your customer) that something has an effect, even though it hasn't.
However, the decrease in statistical power is still quantifiable, and with the right math you can still calculate an accurate 95% confidence interval on the effect size (which will be much wider than the wrong math where you naively don't account for the "peeking"). And of course, it's totally possible that the treatment is so effective that even the accurate calculation shows that the lower bound on the effect size is so much higher than the control group that the responsible thing to do is to stop the trial early.
Here's some the math on how much lower the statistical power is if you "peek": https://www.evanmiller.org/bayesian-ab-testing.html
I read HN regularly, but for health and biology related information, I'd much rather turn to the various professional communities on Twitter. HN is at best "Lies my Bio 101 Professor Told Me" most of the time, and at worst a worked example of physicist/engineer's syndrome.
Is there much value in an ad-hominem reply?
Or in generalizing it to an entire community? The irony seems hard to avoid when such a generalization is made without mentioning any statistical foundation, while pontificating about statistics.
> Or in generalizing it to an entire community?
I don't like this style either but sometimes I think we deserve it for being a smug echo chamber.
Basically, much the same thing could have been said in a different way and I would have upvoted it.
This and more. Almost every comment here is made with absolute confidence and authority, much more than is warranted. The tone of the person who said that "it's a great way to commit statistical fraud" without a caveat sounded like a know-it-all who knows better than the FDA and the scientists who made this cure in the first place or that they're outright unethical.
Most times such comments get upvoted. Sometimes they get downvoted when they're called out on their BS. So there's some balance.
I could add quite a few more generalisations myself while I'm at it, HN isn't solely populated by hyper intelligent, well reasoned, logical doctors, who form their ideas completely independently of everyone else. There's going to be group think, there's going to be like minded individuals attracted to one another, that's human nature, deal with it.
I don't even think it's an ad-hominem. HNers are generally argumentative gits (generalisation), who like finding an exception/hack/new way of looking at something (generalisation). I have no problem with some of those schemes being described as 'hairbrained' (sic although actually... ), but that's why I come here, because if people didn't think that way they wouldn't be Hackers.
Not sure if that was for comedic effect but I laughed out loud! A brilliant demonstration of the behaviour you describe.
Additionally, my understanding from a quick read is that the SPMS trials were aiming to delay progression in disability, rather than eliminate the effects altogether. That seems trickier to measure, and also more subject to just... not spending enough time looking at it.
Ebola, on the other hand, has a binary outcome (dead vs cured) with a timeline of a couple weeks, IIRC.
Doesn't it leave (cured) people potentially permanently damaged as well? eg whatever organs were damaged, are still damaged
Are you talking about the European trial, referring to “358 patients with SP-MS were allocated placebo and 360 were allocated interferon beta-1b; 57 patients (31 placebo, 26 interferon beta-1b) were lost to follow-up.”?
If so, your interpretation isn’t quite right. It’s not saying they stopped 57 patients short, it’s saying those 57 people didn’t participate at all, but that’s irrelevant to the early ending. The trial stopped short of it’s intended completion time, not short of a number of patients. The blog post indicates it was stopped 2 years early, out of a planned 2-3 year study period.
> the reason the first trial came to an exaggerated impression seemed to be the number of patients who might not have fully progressed to SPMS
Stopping early can lead to statistical fraud, which is why the bar is so high on doing so. But it has to be balanced with the recognition that, if the interim results are correct, continuing the trial will lead to a significant number of avoidable deaths.
And for what it's worth, given the believed cause of the flawed trial being cited, it sure sounds like if the trial had run to its conclusion it still would have produced flawed results.
I can give some hare-raising examples but for obvious reasons... The one I can give is it was known that docs who prescribed this to multiple patients and saw an apparent improvement the attributed to the new drug, would switch the patients on the old drug to the new and not inform us. Obviously they couldn't or they'd invalidate the trial and they knew it. And it was done entirely with the patient's best interests at heart. Docs care about their lives.
That may have been rare and a flaw in the trial protocol, but much worse stuff was done via utter incompetence. And I mean including at the top of these giant drug companies. Run by idiots, really.
Wider lesson: just cos you hand over a process to a third party does not mean it's going to be done right.
 tribute to the thread elsewhere
It's supposed to be hair-raising because it's alarming and surprising etc. Nothing to do with taking care of hares :)
In general it’s worth remembering that RCTs are estimating the effect of an intention to treat ( the randomisation) not the treatment itself.
If the doc correctly divines that the drug is improving things, yes, but there is noise in the signal so it may be just noise causing the few apparent improvements the doc sees. If so, doc's action may be smothering a less-then-obvious signal.
There's too much at stake for that to be acceptable.
> ...are estimating the effect of an intention to treat ( the randomisation) not the treatment itself.
I don't understand - the protocol applies the drug (aka the treatment) and results are measured. I don't understand 'intention to treat'. What is 'intention' here, so tech term I am not familiar with?
There are 6 possibilities:
1- stop early, effective
2- stop early, ineffective
3- passed all trials, effective
4- passed all trials, ineffective
5- failed trials, effective
6- failed trials, ineffective
Assign a utility value (lives saved, risks, cost,...) and a probability to each situation and do the maths.
P(1) = P(3) + P(5)
P(2) = P(4) + P(6)
So, if (P(3) + P(5))U(1) + (P(4) + P(6))U(2) > P(3)U(3) + P(4)U(4) + P(5)U(5) + P(6)U(6) it is better to stop early.
The risk of fraud can be taken into account.
Really, the whole drug approval process is filled with uncertainty. Partly it's how the sausage is made in biotech, but also pharma companies love this method as it allows them to put forward non-inferior drugs with higher margins. We can reform the process, and should, but there will still be statistical uncertainty for 100's of new candidates, until they reach the post-market study phase.
It can be important to ethically stop a trial based on the information available, even if the information available later turns out to be incorrect.
Heck, a lot of recent work on novel trial designs like stepped-wedge are specifically designed to balance equipoise and statistical needs.
edit: The 6% figure is population restricted to early interventions. I am uncomfortably out of my limited knowledge here, but I think that early intervention numbers are better across the board. I'd want to compare the 6% number to the control. And I don't want to see a control! It is such a good result no matter how you look at it that they wisely halted the trial.
In other words, cure is probably the right word, just not for everybody.
Although if I were to die from it I wouldn't probably be able to call it anything.
Toxic epidermal necrolysis, a severe form of Stevens-Johnson Syndrome, has about a 30% mortality rate. I understand it to be a first world problem typically caused by taking certain strong medications. It's a severe and often deadly allergic reaction.
(I'm not going to provide links because both Wikipedia entries have disturbing photos. I've verified that I'm spelling both correctly so you can google it if you want. However, you probably would be hard pressed to find an article about either condition that didn't have similarly graphic photos.)
To clarify: epidermal means it's a skin condition. Skin conditions that kill people tend to not be pretty and the symptoms are highly visible.
"necro" -- "death"
"lysis" -- "busting open"
"epidermal" -- "skin"
"syndrome" -- "no known cause"
However, it's a little unclear why TEN is a point of comparison to Ebola, as one is a transmissible disease and one is something that happens to unlucky people typically in response to common small-molecule drugs. I guess TEN sounds like a probable side effect of antiviral immune therapy, but it's not mentioned in the article. And it seems a little tricky to separate the side effects from the disease when dealing with hemorrhagic diseases in particular
So while it is often the case that when a syndrome is initially named its cause is unknown, the two are really referring to different levels of abstraction of a disease. The syndrome is its effects, irrespective of whether we know its cause.
Edit: one usage is for a set of commonly concurrent symptoms, possibly with no known cause. Another common usage is a set of concurrent symptoms with multiple known causes (e.g. toxic shock syndrome).
Toxic epidermal necrolysis (TEN) is the most lethal on a scale of 4 related necrotic skin conditions: TEN, SJS, EMMajor, EMMinor. The medical industry sees all 4 as kind of a sliding scale, similar to how burns are classified as different degrees and can be clinically distinguished but are still burns. They are categorized based on the percentage of your skin that becomes necrotic, and additionally which tissue types are affected.
My understanding is that herpes is one of the most common causes, although maybe that's only true for EMM and not TEN/SJS. For some reason, as we age, sometimes our body changes its reaction to herpes or other infections, becoming hypersensitive, resulting in one of the 4 previously mentioned necrotic skin conditions.
I'm sharing this, because even though my symptoms were literally staring the doctors in the face, it took years before a studious dermatologist figured out I had recurrent EMMajor. If you have "cankers" or "rashes" associated with your herpes outbreaks, ask your doctor about it, even if the rashes aren't painful. Recurrent EMMajor can be life-threatening without treatment and can progress with further attacks.
https://www.nhs.uk/conditions/erythema-multiforme/ (warning: disturbing pictures)
For those bipolar folks out there, remember even lamotrigine can cause SJS (still very rare), which is why you should always ramp up the dose gradually. 
That's a small sample, but only an 18% mortality rate with the best available treatment, before this cure.
The 6%-figure was for a sub-population of victims who received one of the treatments early. There's probably a sub-sub-population of young-adult victims who're in good health and received early treatment who had a near-0% rate, too.
From glancing at Wikipedia's numbers, it seems that the average Ebola victim faces about 50% odds, so this'd improve that to about 29%.
But, with-or-without this treatment, people who receive care, especially early, enjoy better odds than their peers who don't.
> The monoclonal antibody cocktail produced by a company called Regeneron Pharmaceuticals had the biggest impact on lowering death rates, down to 29 percent, while NIAID’s monoclonal antibody, called mAb114, had a mortality rate of 34 percent. The results were most striking for patients who received treatments soon after becoming sick, when their viral loads were still low—death rates dropped to 11 percent with mAb114 and just 6 percent with Regeneron’s drug, compared with 24 percent with ZMapp and 33 percent with Remdesivir.
Wired.com is almost literally unreadable. It's a caricature of all that's wrong with modern web design. Is everyone else seeing what I'm seeing? http://u.cubeupload.com/temp9871/wired.png
There are other options -- Reader View in Firefox and w3m in console are two I use frequently. For browsers other than Firefox, Outline is useful and I'm grateful it exists.
Not quite - you forgot the GDPR popup on top of the subscribe popup, as well as the autoplaying video ad with sound!
What makes Ebola so dangerous is the ease at which infection spreads within the medical staff and how quick it can occupy all your beds and "simple" IV devices.
Depending on how it is made, a cure may not change much. If it relies on medical attention, then it probably won't change the high death rate of people outside medical care, which is what allows an epidemic to start.
WIRED: EBOLA CURED
It's used a lot in Youtube comments and it weirdly grates me.
With a polyclonal, manufacturers would need to prove safety on every single antibody and guarantee composition of the mixture.
Ebola's a viral infection, like the common cold or the flu. If someone gets sick with it, then usually their immune system should fight it off naturally, just like the common cold or the flu. And just like a cold/flu, there hasn't really been a cure for it; instead, Ebola sufferers would be put on bed-rest with fluids to resist dehydration, fever management, etc., while the body fights it off.
However, Ebola's symptoms tend to be severe. Glancing at Wikipedia's figures, it seems that about 50% of people who get it die -- which probably varies a lot by the exact strain, health of the victim, support received while sick, etc.. Many victims end up making a full recovery, though some end up taking more long-term damage from the trauma.
As I'm reading it, they've observed that some victims tend to fight off Ebola with relative success. So, they appear to be trying to copy those survivors' defenses via [monoclonal antibodies](https://en.wikipedia.org/wiki/Monoclonal_antibody), then pass that on to Ebola sufferers.
Since they're basically optimizing a victim's immune system with specially selected antibodies, the victim still suffers Ebola and fights it off as usual, just they're getting some pretty powerful backup in that fight.
And apparently the results are pretty good so far! The article reports:
The article exaggerates a bit by citing the mortality rates for people who don't receive any support; that seems like an unreasonable figure since this treatment is an advanced form of support, so presumably it'll improve the odds of those who do get support.
So, if mortality rates are about 50%, then presumably they can drop that to about 29% overall, with people who seek treatment earlier enjoying the greatest benefit with mortality rates dropping to 6%.
Realistically speaking, this seems to suggest that this "cure" reduces an individual's odds-of-death by a bit shy of 50%; that leaves a lot to be desired. Still, it's awesome because:
1. Any progress on something like this is awesome.
2. This sort of technology can rapidly improve, so the current positive results may just be the beginning.
Someone in your family, or village shows symptoms of Ebola. You get them diagnosed ASAP and there's still a one in three chance you're never going to see them again.
However, a confirmed case now has everybody's attention. Everyone who was exposed now has a 94% chance of surviving. Double the morbidity of the swine flu, yes. Still a quite stressful time for everybody, full of uncertainty and loss. But not the cultural-PTSD-inducing, apocalyptic catastrophe it was before.
What I am specifically interested in is whether the rate of new infections can be curtailed to below the self-sustaining threshold.
Wouldn't that give the best results?
Maybe never. A lot of time in any case, probably. Ebola is a plant's virus adapted to trees. Evolved to use bats (and probably arboreal snakes also) but can't survive for a long time in primates, and can't survive in soil at long term. We are a dead end for it. Would need infected humans munching some inedible leaves of a tropical tree or visiting hollow trunks where bats live.
News cases of Ebola in the future will be from a new strain, but this does not imply evolution or resistance. Is just that the number of ebola specimens in contact with humans is limited.
What is notable about Ebola is that its virulence keeps dropping while its ability to spread has significantly increased. The larger issue is that Ebola is in areas that don't have the resources to handle any serious outbreak. It's becoming more likely that Ebola is going to be self sustaining soon.
I'm kind of amazed that a comment expressing interest in when this therapy will be obsolete, see that 96% of bacteria are resistant to Penicillin G now, gets a negative response. Drugs are only effective when the pathogen is still sensitive to them.
If everyone on penicillin was kept in an isolation chamber, the effectiveness over time would be different.
While partial resistance can be encouraged in a single person, that doesn't matter if it dies inside them. And if a resistance mutation happens in the wild, away from drugs, there's no reason to expect it to spread at all.
I never heard that and I can't find that in Wikipedia. Do you have a link with more information about that?
Ebolavirus is a genus comprising at least five species that can create similar outbreaks. I don't know if the treatment protects from all of them (Probably not). Is a fast mutating kind of creatures also. I guess that each future outbreak will need to rebuild an specifical treatment. The good news is that we know how to rebuild it fast, there is a new awareness of the problem, and african people are fixing some cultural traditions that helped to spread the virus in the past.
There are also other two genuses closely relative to Ebolavirus: Marburgvirus (produces a similar haemorrhagic fever in humans), and the spanish surprise Lloviu cuevavirus (poorly known but assumed harmless). Treatment designed for Ebola probably will not protect from Marburg disease, but I'm speculating.
It is why flu vaccines can be ineffective by the end of the flu season. It takes about 2 weeks to grow a flu virus in sterile eggs, the most "high tech" solution known to man currently. Every time someone with flu sneezes, they are emitting new multiple strains of the flu virus.
The other problem with Ebola is it can hide in parts of the body where the adaptive immune system does not work, places like the eye and testes. So even though the virus may not show up in test results, it could reappear when someone's immune system is weakened sometime in the future. There are other ways to kill it though. Just for reference, someone I know works at Porton Down in the UK, MOD facility, they told me Ebola is nothing compared to some of the viruses and bacteria they have in their facilities. In other words there are far worse things to be worried about than Ebola.
In practice, it'll probably work out to be sorta like the issue with flu vaccinations, where health organizations will have to predict which strains are likely to be out there and then prepare accordingly.
Still, even if Ebola somehow rapidly evolved to completely ward off the current treatments, it's moreso the technology that created these treatments that's a breakthrough. So, if Ebola adapts, presumably they'd just update the treatments.
That said, the current treatments probably aren't very optimized yet, either. These are early successes; future results seem liable to be much better.
There has never been a better time to be alive. We're so lucky.
Ebola is now Curable (YC 17)
If your were not making this point, then I don't have the answer. :-)
That doesn't sound like a "cure" to me. Significant progress to be sure, but in my mind to be considered a "cure" the mortality rate would have to drop to near zero.