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Life After Eroom’s Law

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Re: Life After Eroom’s Law

#11

Post by rossdavidh »

Elephant in the room: what was it you thought would stop it? If I have a great new idea for a high-performance computer chip, which would also cause them to be twice the cost, it won't get funded, because people will just settle for a higher performance chip in a few years at a lower cost.

In the case of medicine, as society gets wealthier, it is willing/able to spend more on medicine. The only time you say "no thank you" to an improvement in medicine in exchange for higher costs, is when you're out of money.

There is no such thing as "good enough" medicine, since we all still die eventually. Therefore, we pay more for medicine, including pharmaceutical R&D, because we can, and we can never actually get as much as we want.

Re: Life After Eroom’s Law

#12

Post by refoundable »

rossdavidh wrote: post #11

Elephant in the room: what was it you thought would stop it? If I have a great new idea for a high-performance computer chip, which would also cause them to be twice the cost, it won't get funded, because people will just settle for a higher performance chip in a few years at a lower cost. In the case of medicine, as society gets wealthier, it is willing/able to spend more on medicine. The only time you say "no thank…

Most people tend to focus on the cost side of Eroom's law, but I find its most disturbing implication to be the other side: That between 1950 and 2010, we got ~100x worse at finding drugs that actually work.

That suggests that there's something deeply broken about the science, and not just about the regulation or the cost structure.

Re: Life After Eroom’s Law

#13

Post by Dysseus »

refoundable wrote: post #12
rossdavidh wrote: post #11

Elephant in the room: what was it you thought would stop it? If I have a great new idea for a high-performance computer chip, which would also cause them to be twice the cost, it won't get funded, because people will just settle for a higher performance chip in a few years at a lower cost. In the case of medicine, as society gets wealthier, it is willing/able to spend more on medicine. The only time you say "no thank…

Most people tend to focus on the cost side of Eroom's law, but I find its most disturbing implication to be the other side: That between 1950 and 2010, we got ~100x worse at finding drugs that actually work. That suggests that there's something deeply broken about the science, and not just about the regulation or the cost structure.

Could you expand a bit on that?

I'm having a hard time making the connection between declining efficiency and there necessarily being something broken about the science.

To expand just a bit: Scannell seems to be primarily focused on the disease model as the root issue here. This is curious to me. My understanding is that drugs fail primarily in two ways:

1) It's ineffective - fails to treat the disease. Which is partially covered by model validity, but also impacted by pharmacokinetics and distribution. Essentially your molecule can work, it just can't get where it needs to go in a high enough concentration to make a difference.

2) It's unsafe - your molecule is toxic either acutely or long term.

The data[0] I'm aware of indicates that these issues occur with roughly equal frequency. (My assumptions being: failure in Phase 1 trials are an issue of safety, failure in phase 2 can be caused by safety or effectiveness). Which for me calls into question the focus solely on good disease models.

[0] https://www.nature.com/articles/nrd3078

Re: Life After Eroom’s Law

#14

Post by scythe »

>Generally, he’d get the same kind of answer: the industry had run out of “low-hanging fruit.”

>In the course of his own later investigations, Scannell began to focus on a serious technical problem called “model validity,”

(Sentences adjacent in original.)

The problem, here, I think, is backwards. I have a little window into the world of drug discovery by a decade-long interest in nootropics (tl;dr: I don't take them anymore).

These statements aren't wrong, but they obscure the history. The way we discovered antidepressants was mostly like this:

- tuberculosis patients treated with hydrazines become "inappropriately" happy

- modified hydrazines first used to treat depression

- hydrazines shown to increase serotonin levels by monoamine oxidase inhibition, now called MAOIs

- serotonin hypothesis of depression developed

- serotonin-targeting drugs developed for depression

There are a few more steps here, but the point is: the low-hanging fruit was the hydrazine, then we climbed the tree and got SSRIs.

The problem is that we started climbing all the trees with low fruit but never developed a way to find new trees. We also stopped looking for low-hanging fruit, in that we don't test random drugs on people the way we used to in the '40s. Everything has to be justified by an existing theory even though the existing theories are nowhere near comprehensive or complete.

I don't think we should start testing random drugs on people, but I do think we need to avoid this framing of the problem. We don't understand human biology that well. Our primary focus needs to be not on developing drugs per se but on understanding the extremely intricate hydrogen-bonded nanomachines they're supposed to modify.

But relative to that, our efforts to find drugs should be tempered by a certain humility about the validity of even our most "well-understood" theories. Most of them were developed by accident. The whole risk-averse investing and management apparatus wants reliable theories, so researchers need to be louder about the fact that in many biology problems we don't have reliable theories. We have moderately supported working models.

Re: Life After Eroom’s Law

#15

Post by light_hue_1 »

Dysseus wrote: post #13
refoundable wrote: post #12

Earlier quoted context omitted.

Most people tend to focus on the cost side of Eroom's law, but I find its most disturbing implication to be the other side: That between 1950 and 2010, we got ~100x worse at finding drugs that actually work. That suggests that there's something deeply broken about the science, and not just about the regulation or the cost structure.

Could you expand a bit on that? I'm having a hard time making the connection between declining efficiency and there necessarily being something broken about the science. To expand just a bit: Scannell seems to be primarily focused on the disease model as the root issue here. This is curious to me. My understanding is that drugs fail primarily in two ways: 1) It's ineffective - fails to treat the disease. Which is par…

Two things, one is that toxicity is overwhelmingly the failure mode and the other is that 1 (effectiveness) and 2 (toxicity) are actually closely related not independent.

Failures are overwhelmingly in Phase II, https://en.wikipedia.org/wiki/Phases_of_clinical_research And we know why they happen, we don't need to guess. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609997/#:~:tex... Mostly it's that we discover previously unknown toxic effects. Between Phase I failures due to toxicity, Phase II failures which are half due to toxicity, and Phase III failures, and Phase III trails failing 17% of the time due to toxicity https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092479/ it is overwhelmingly the biggest problem. Only half of Phase III trials fail due to a lack of efficacy.

At the same time effectiveness and safety are not independent variables. Safety often a matter of dose. The dose required to achieve a clinical effect may turn out to be unsafe.

The issues goes back largely to model validity. That our models don't allow us to accurately establish safety margins and dosages, in addition to often being misleading about the wider effects that drugs will have.

Re: Life After Eroom’s Law

#16

Post by refoundable »

Dysseus wrote: post #13
refoundable wrote: post #12

Earlier quoted context omitted.

Most people tend to focus on the cost side of Eroom's law, but I find its most disturbing implication to be the other side: That between 1950 and 2010, we got ~100x worse at finding drugs that actually work. That suggests that there's something deeply broken about the science, and not just about the regulation or the cost structure.

Could you expand a bit on that? I'm having a hard time making the connection between declining efficiency and there necessarily being something broken about the science. To expand just a bit: Scannell seems to be primarily focused on the disease model as the root issue here. This is curious to me. My understanding is that drugs fail primarily in two ways: 1) It's ineffective - fails to treat the disease. Which is par…

The FDA does not allow Pharma companies to create safe and slightly less effective drugs than the best-in-class, even if such drugs were 10-100x cheaper and would thus alleviate most people's complaints about outrageous drug prices.

Scannell's observations are focused on the problem of finding drugs that are more effective than the current best-in-class, the so-called Better than the Beatles problem.

This turns out to be a really hard search problem, given for instance that animal models make unreliable and poor substitutes for humans beings, or that you're generally not allowed to base drug approval on small but highly representative patient populations (with some exceptions). There are even more technical problems I won't get into here (see Question 9 in the interview).

In short, I see no reason why we couldn't be getting slightly less effective but way cheaper drugs today if the FDA was willing to slightly relax its use of the precautionary principle. But in order to keep pushing the frontier of drug efficacy, we'll need new technical breakthroughs to help us solve the search problem.

Re: Life After Eroom’s Law

#17

Post by Dysseus »

light_hue_1 wrote: post #15
Dysseus wrote: post #13

Earlier quoted context omitted.

Could you expand a bit on that? I'm having a hard time making the connection between declining efficiency and there necessarily being something broken about the science. To expand just a bit: Scannell seems to be primarily focused on the disease model as the root issue here. This is curious to me. My understanding is that drugs fail primarily in two ways: 1) It's ineffective - fails to treat the disease. Which is par…

Two things, one is that toxicity is overwhelmingly the failure mode and the other is that 1 (effectiveness) and 2 (toxicity) are actually closely related not independent. Failures are overwhelmingly in Phase II, https://en.wikipedia.org/wiki/Phases_of_clinical_research And we know why they happen, we don't need to guess. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609997/#:~:tex... Mostly it's that we discover prev…

I think we're saying the same thing. The disease model itself is necessarily limited. Sure you have a molecule that hits the target, great. But the struggle comes from being able to get that molecule to target in vivo without causing toxic effects.

Maybe we're just missing on how we're using words. I don't see how having a better disease model necessarily gets you to a better place on this. Sure, you can get better SAR and can decrease the dose. But as you point out, dosage is not just a function of SAR.

Having better tox models seems like the highest value, albeit very difficult, route here. Which to me is a separate, more general, problem than a specific disease model.

Re: Life After Eroom’s Law

#18

Post by refoundable »

scythe wrote: post #14

>Generally, he’d get the same kind of answer: the industry had run out of “low-hanging fruit.” >In the course of his own later investigations, Scannell began to focus on a serious technical problem called “model validity,” (Sentences adjacent in original.) The problem, here, I think, is backwards. I have a little window into the world of drug discovery by a decade-long interest in nootropics (tl;dr: I don't take them…

I agree that discovery is far from a straight-forward process, and that many of the cavalier ways in which it happened in decades past would be criminally prosecuted and beyond the pale today.

But I don't think that there was ever much low-hanging fruit to begin with. Discoveries always look "obvious" ex post and almost never ex ante.

I find it best to think of "low-hanging fruit" as a euphemism that polite people have agreed to use in order to excuse the massive failure that has taken place and stop curious people like Scannell from asking too many questions.

Re: Life After Eroom’s Law

#19

Post by tehjoker »

refoundable wrote: post #16
Dysseus wrote: post #13

Earlier quoted context omitted.

Could you expand a bit on that? I'm having a hard time making the connection between declining efficiency and there necessarily being something broken about the science. To expand just a bit: Scannell seems to be primarily focused on the disease model as the root issue here. This is curious to me. My understanding is that drugs fail primarily in two ways: 1) It's ineffective - fails to treat the disease. Which is par…

The FDA does not allow Pharma companies to create safe and slightly less effective drugs than the best-in-class, even if such drugs were 10-100x cheaper and would thus alleviate most people's complaints about outrageous drug prices. Scannell's observations are focused on the problem of finding drugs that are more effective than the current best-in-class, the so-called Better than the Beatles problem. This turns out t…

The costs of drugs is usually profit seeking. Many drugs can already be produced and delivered cheaply if the economic system would allow it. Trying to patch the drug instead of the economics just gives people worse drugs.

Re: Life After Eroom’s Law

#20

Post by refoundable »

Dysseus wrote: post #17
light_hue_1 wrote: post #15

Earlier quoted context omitted.

Two things, one is that toxicity is overwhelmingly the failure mode and the other is that 1 (effectiveness) and 2 (toxicity) are actually closely related not independent. Failures are overwhelmingly in Phase II, https://en.wikipedia.org/wiki/Phases_of_clinical_research And we know why they happen, we don't need to guess. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609997/#:~:tex... Mostly it's that we discover prev…

I think we're saying the same thing. The disease model itself is necessarily limited. Sure you have a molecule that hits the target, great. But the struggle comes from being able to get that molecule to target in vivo without causing toxic effects. Maybe we're just missing on how we're using words. I don't see how having a better disease model necessarily gets you to a better place on this. Sure, you can get better S…

> Having better tox models seems like the highest value, albeit very difficult, route here. Which to me is a separate, more general, problem than a specific disease model.

Agreed. Better toxicity testing would go a long way towards solving some aspects of the search problem.

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