[mehrshad]

https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarte...

"Despite being described as a “cabal,” the amyloid camp was neither organized nor nefarious. Those who championed the amyloid hypothesis truly believed it, and thought that focusing money and attention on it rather than competing ideas was the surest way to an effective drug.

It has not worked out that way. Research focused on amyloid, and the development and testing of experimental drugs targeting it, have sucked up billions of dollars in government, foundation, and pharma funding with nothing to show for it. While targeting amyloid may or may not be necessary to treat Alzheimer’s, it is not sufficient, and the additional steps almost certainly include those that were ignored, even censored. Probably the most shattering turn came in March, when Biogen halted the study of what proponents called the most promising Alzheimer’s drug in years — an amyloid-targeting antibody."

I still refer to this article seven years later. Groupthink in the medical research space sets back progress by decades. And it's not just Alzheimers. The FDA's approval process is stymied by a CYA culture that fails to adopt the risk profile it needs to in order to potentially save large contingents of sick and dying.

[cpgxiii]

> The FDA's approval process is stymied by a CYA culture that fails to adopt the risk profile it needs to in order to potentially save large contingents of sick and dying.

Except the history of FDA approval here is that it has been too accepting of drug candidates for Alzheimers with very weak evidence of efficacy and serious side effects. This particular field would probably be better off if the FDA took a harder position on efficacy, rather than deferring to drug companies and patient/caregiver groups that desperately want something.

[londons_explore]

I would like to see the FDA get rid of their binary "Approved" approach.

Instead, at the start of a treatment on a patient, an analysis must be done of all available data, and the treatment only allowed if the error bars put it within the realm of the best treatment available.

That means at the start when not much data is available, it is easy to give it to a patient. But over time as more data comes in it gets harder and harder to do so if the treatment is ineffective or harmful.

Data should be collected and analyzed in real-time - it should be a matter of hours between some life event like a death feeding into the dataset used for decisions on new patients.

[StableAlkyne]

The struggle is the high level regulatory bodies (with the exception of aberrations such as the current admin's approach to appointment) generally select for individuals with a low risk tolerance. Low risk tolerance is generally incompatible with speed - it's a miracle the covid vax and treatments were approved as quickly as they were in 2020.

Biggest example of this risk aversion is the peptide craze going on (the most famous of which are GLP-1 antagonists). It's pretty much a wild west where people read a low-sample animal study, and buy a drug that's "for research only, not for human consumption" off of a compounding pharmacy in China.

Few human studies because even if you have willing and enthusiastic volunteers it's too expensive and creates legal liability. And the FDA cannot approve it without a high bar of evidence (for effective treatment and low risk) and costly, time consuming reviews. Because of this, there is a black market for the things and people are basically being their own test subjects.

[mft_]

> The struggle is the high level regulatory bodies (with the exception of aberrations such as the current admin's approach to appointment) generally select for individuals with a low risk tolerance.

This may be true, but I don't think it's the major driver of conservatism. Two thoughts/observations:

1) Bodies like the FDA face a strongly skewed set of incentives. If they take a risk on something and people get hurt, they face huge public criticism. If they take a risk on something and it's all fine, very few people care or notice. As such, they are strongly driven to not make a public mistake - which drives ever more conservatism.

2) FDA can actually be innovative compared to other health authorities. Breakthrough therapy designation, Project Optimus, Project Frontrunner, and others - show this. However, they've got a strong 'not invented here' mindset - they flatly refuse well-meaning individual innovations from pharma companies, if they're not compatible with FDA's guidelines. And they're heavily bureaucratic, meaning the innovations that do appear are usually following years of process (which probably links back to #1).

[ted_dunning]

What you say is something that is actually already happening.

There is no longer a binary approval/non-approval status. Drugs and treatments that address terminal conditions often get special status. Drugs for rare diseases definitely get special treatment.

In addition, many studies now use continual data collection and evaluation. If the results are very good or very bad, that can be recognized much more quickly and with fewer people exposed to risk than previous types of studies. Reaction to negative events doesn't happen in hours, but it isn't all that far from that.

[jonlucc]

This does happen. SAEs are reported in real time, and they do halt trials sometimes. Also, there is often a condition of approval that requires ongoing data collection for adverse events post-approval.

[snapetom]

I was outraged when I first read that article, but taking a step back and catching up on recent progress, I came to the same conclusion you did. Words like "nefarious", "fraud", and "corrupt" were thrown around, but no one was actively was seeking to do harm.

The harm was done by the groupthink and the sucking up of resources to research alternative causes. One of the comments on HN when that statnews article was first linked was by a commenter who worked on Alzheimer's. They agreed and I remember the line, (something to the effect of) "if you wanted funding for alternative investigations, you had to still throw a bone to beta amyloid in your proposal."

Was it all a waste? No. Current thought is beta amyloid is still involved, but Alzheimer's is multicausal. What those other causes are is in its investigation infancy. We could have started investigating those decades ago if the scientific research complex were truly open to new ideas.

[saadn92]

This is similar to what we see in software architecture. There's a team that picks a framework or pattern early, then builds everything on top of it, and by the time evidence shows up that the foundation was wrong. Now, switching costs are so high that it's cheaper to keep building on the broken foundation than to start over. The amyloid hypothesis reminds me of technical debt. The "cabal" wasn't conspiring, but they were just rationally protecting their sunk costs, same as any engineering org that can't migrate off a bad database choice.

[Maxion]

There's a lot of this going on in science. Once the common accepted truth is "X" papers that are counter to X or show that X is not true, end up not getting published and then funding dries up.

[SwtCyber]

The scary part is that everyone can be acting in good faith and still produce a monoculture

[Aperocky]

They say science advance one death at a time.. let's hope LLM/AI can fix that by giving resource previously inaccessible to smaller players to be able to show results against the consensus.

Otherwise we just need to hope that we live long enough and don't catch ALZ until the current ruling peer group pass.