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Two decades of Alzheimer's research may be based on deliberate fraud that has cost millions of lives
Over the last two decades, Alzheimer's drugs have been notable mostly for having a 99% failure rate in human trials. It's not unusual for drugs that are effective in vitro and in animal models to turn out to be less than successful when used in humans, but Alzheimer's has a record that makes the batting average in other areas look like Hall of Fame material.
And now we have a good idea of why. Because it looks like the original paper that established the amyloid plaque model as the foundation of Alzheimer's research over the last 16 years might not just be wrong, but a deliberate fraud.
The suspicion that something was more than a little wrong with the model that is getting almost all Alzheimer's research funding ($1.6 billion in the last year alone) began with a fight over the drug Simufilam. The drug was being pushed into trials by its manufacturer, Cassava Sciences, but a group of scientists who reviewed the drug maker's claims about Simufilam believed that it was exaggerating the potential [...] and hired an investigator to provide some support for this position.
[...] In 2006, Nature published a paper titled "A specific amyloid-β protein assembly in the brain impairs memory." Using a series of studies in mice, the paper concluded that "memory deficits in middle-aged mice" were directed caused by accumulations of a soluble substance called "Aβ*56." [...]
That 2006 paper was primarily authored by neuroscience professor Sylvain Lesné and given more weight by the name of well-respected neuroscientist Karen Ashe, both from the robust neuroscience research team at the University of Minnesota. [...]
The results of the study seemed to demonstrate the amyloids-to-Alzheimer's pipeline with a clarity that even the most casual reader could understand, and it became one of—if not the most—influential papers in all of Alzheimer's research.[...]
What intrigued Schrag when he came back to this seminal work were the images. Images in the paper that were supposed to show the relationship between memory issues and the presence of Aβ*56 appeared to have been altered. Some of them appeared to have been pieced together from multiple images. [...]
Now Science has concluded its own six-month review, during which it consulted with image experts. What they found seems to confirm Schrag's suspicions.
They concurred with his overall conclusions, which cast doubt on hundreds of images, including more than 70 in Lesné's papers. Some look like "shockingly blatant" examples of image tampering, says Donna Wilcock, an Alzheimer's expert at the University of Kentucky.
[...] And it seems highly likely that for the last 16 years, most research on Alzheimer's and most new drugs entering trials have been based on a paper that, at best, modified the results of its findings to make them appear more conclusive, and at worst is an outright fraud.
Some interesting stuff between the [...] was cut down for this summary, so I recommend reading the linked story. I also coincidentally just listened to the most recent Science podcast where they go into this in much greater detail and is well worth a listen. [hubie]
(Score: 4, Interesting) by RamiK on Sunday July 24 2022, @09:31AM (6 children)
The short-sellers didn't have a financial interest to pay for the peer-review investigation until the drugs were approved by the FDA.
This is a pretty interesting case study for Milton Friedman's argument against the FDA: The original argument said it's possible more people are harmed by the delays the FDA causes in allowing good drugs than by the good they do in blocking bad drugs. Now, we have a fairly complex example showing the an even worse implication of slow and expensive regulations: If the research would have led to early drug development, it would have failed in the market (either short sellers or when being used in the community) and two decades of research wouldn't have been sent down the drain. Sure, some people would have been hurt from the new and useless drugs' side-effects. Maybe there would have even been fatalities. But, two decades of science and a generations of medical research is such a huge loss for any field that it's likely would have been worth it.
Regardless, peer-review, as tool for science, failed.
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(Score: 4, Interesting) by quietus on Sunday July 24 2022, @02:39PM (5 children)
If you’d take the matter seriously, you might at least have read the dailykos article. The research was ordered when the results of stage II trials were published i.e. long before FDA approval; and if you’d casually checked the involved company’s Wikipedia entry you’d have noticed the company has great difficulty getting such approvals, as in getting no approvals at all in their whole history.
How you get from there to turning the FDA into the villain of the piece is anybody’s guess, but I suspect a copy of Atlas Shrugged and a high dose of opioid painkillers might have done the trick.
(Score: 3, Insightful) by RamiK on Sunday July 24 2022, @04:25PM (4 children)
Why does that matter when it took short-traders to start the investigation rather than the FDA or peers? That is, the FDA regulations failed since the FDA only makes sure companies report they've gone through the motions rather than actively try and duplicate their results using FDA run labs while the peer review failed since the original papers were never duplicated by other scientists.
So, all-in-all, the paper-to-market process as going through both peer-review and FDA regulations, is a rubber-stamp.
How did my "interesting case study" turn into villainizing the FDA? All I'm saying is that, where Friedman only (rhetorically) considered how many people die from bad drugs vs. how many people die from waiting for the approval of good drugs, we now have another factor to consider: How much medical science itself suffers when a whole field wastes over a decade on a faulty theories.
But to give a more concrete example of Friedman's argument, imagine how many people would have died if the FDA wasn't ordered to fast-track the COVID-19 inoculations. What if instead of months, it would have taken years? How much damage did the bad J&J and ilk inoculations caused compared to the lives that would have been lost if Moderna and Pfizer would have been delayed? Extending on that, how many years of research would have been lost on old inoculation technologies while waiting?
Eh, while a free market libertarian solution where adversarial labs could be funded and run by shorts traders and competing companies might be an interesting game theory experiment, my solution to the faulty FDA and peer-review process isn't to loosen the regs but to nationalize the whole pharmaceutical industry, peer-review process and approval procedures by having the government directly fund thousands of labs at what would probably be the single greatest expenditure ever. I admit I never took political science classes, but I'm pretty sure that's one step beyond socialism straight into communism.
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(Score: 3, Informative) by quietus on Sunday July 24 2022, @06:56PM (3 children)
The FDA repeatedly prevented this company bringing drugs to market because they either didn’t consider their research valid or considered the side effects too serious: how can you call that a failure of the FDA?
It is not the role of the peer review process to reproduce the research described in a scientific article: that’s the role of the wider scientific community and the reason why the concept of a hypothesis is central to hard science.
The short-tracking of covid vaccines had little to do with skipping FDA regulations: the only thing what happened is that the different stage trials ran in parallel instead of sequential. The reason these normally run in sequence is to catch negative side effects as early as possible, and not putting larger sample sizes in harm’s way. Pharma companies (J&J, at least) already were thinking aloud of doing this themselves before gov’t started shuffling money towards them.
Finally, it wasn’t professional hedge fund short traders who stirred the proverbial pot here: but a bunch of scientists who bought shorts and paid a piffle amount of money to another scientist to put their complaint against the NIH on solid administrative grounding.
(Score: 2) by RamiK on Sunday July 24 2022, @07:51PM
It's a "The operation was successful, but the patient died" type problem: The FDA and publicist' editors are fulfilling their intended roles, but they're failing at their intended purpose due to how their roles are set out. That is, it's a policy failure. You can compare it to the war on drugs where even if educators, police, judges and prisons are all doing their jobs, the result is a failure because the premise itself is folly. Here, the problem is that the government reached for all the easy pickings, and left the real hard work - providing incentives for research duplication - to the charity and short traders. Worse, the FDA and publications are providing a false sense of assurance regarding the validity of products and research: The reason the FDA managed to stop certain drugs from reaching the markets entirely depends on the results reported by the companies themselves. A bad actor can, and does circumvent the checks. Just like how the opioid overdose epidemic kept claiming lives and everyone shrugged saying they it's not their fault.
Who do you think does all that bioinformatics and engineering consultancy for hedge funds? MBAs, lawyers and stats majors? Hedge funds hire engineers and scientists full-time and contractually-consultancy to review patents as standard practice. Whether these guys are otherwise working academic / private researchers and only do the consultancy and investing as side-gigs makes no difference whatsoever. It's still a market incentive that only barely stopped the FDA's approval and was a good decade too late in taking down the bad paper.
Again, the issue is policy: The research-to-drug system is nothing but useless expensive red tape: Red tape in the form of existing credentials to get a paper publicized by a journal and red tape in the form of money poured into repeat-until-succeed-lab-trials to get the FDA's rubber stamp. All the while, the one factor that can actually stop bad science from getting through - experimental duplication - isn't being funded. And why? Because we're already spending too much on journals and FDA trials. So, yeah, they're not failing at their jobs. It's their jobs that's failing.
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(Score: 2) by Immerman on Monday July 25 2022, @12:40AM (1 child)
>It is not the role of the peer review process to reproduce the research described in a scientific article:
It absolutely is.
>that’s the role of the wider scientific community and the reason why the concept of a hypothesis is central to hard science.
Yes, that is what peer review is.
The review a paper gets before publishing is NOT meaningfully peer review - at best it's a cursory pre-review to reduce the risk of that a journal wastes its readers' time with obviously flawed papers.
(Score: 2) by quietus on Monday July 25 2022, @11:40AM
In a broad sense, you're correct: the actual peer review happens through the scientific community at large through reproduction and extension of previous work. In a narrower sense, however, the term peer review usually refers to editorial review i.e. the reviewing of an article before publishing in a scientific journal. That editorial review is done by sending out the article to a selected group of peers for validation.