6 ms·

Life After Eroom’s Law

55 points by apsec112 6y ago

forgotmypw 6y ago
Does anyone else see a blue background on this page?
- refoundable 6y ago
  No idea what's causing this for you. Can you say a bit more about your setup?
  - cinntaile 6y ago
    Just wanted to say that I enjoyed reading the article. I liked the overall quality and that important bits have citations. I hadn't heard of your website before but I'll be sure to read more of your work in the future.
    - refoundable 6y ago
      Thank you. It takes a fair bit of time to put something like this together, so I appreciate your kind words.
deleted 6y ago
[deleted]
m463 6y ago
"Eroom's law is the observation that drug discovery is becoming slower and more expensive over time"...
- refoundable 6y ago
  A more accurate definition pulled from the introduction: > Eroom’s law is the observation that the cost of developing a new drug roughly doubled every nine years from 1950 through 2010. All in all, it shows a roughly 80-fold decline in the productivity of drug R&D.
  - deleted 6y ago
    [deleted]
refoundable 6y ago
Author here. I interviewed Jack Scannell on the hypothesis that the man who wrote the now famous paper on Eroom's law would likely have many more insights to offer that didn't necessarily make it into print. One of the oddest things about biotech and pharma is that cures trail improvement in technology by at least a couple of decades. That's terrible news if you're a patient/consumer though maybe great news if you're a lab technician.
- beloch 6y ago
  The way your website handles font-size and zoom is really weird.
  - titanomachy 6y ago
    I feel like there should be a named law of hacker news for this. There's sometimes more discussion about how the page doesn't work without javascript, font colors are bad, page is slow, whatever, than about the content of the article. Although in this case most people are talking about the article. Agreed though, there's some weird responsive CSS going on here that makes it impossible to resize fonts on a desktop.
    - refoundable 6y ago
      I echo both observations and urge you to name that law. Will look under the hood at the CSS.
      - jhayward 6y ago
        Thanks for looking. I use the "zoom" feature of Chrome to make fonts more readable. The CSS on this page does not permit resizing of the type - a major faux pas for accessibility. This is a fascinating article, and is even better with the conversation here added. Thanks for your efforts.
- andrewjl 6y ago
  The article mentions poor incentive structure around development of better disease models as an obstacle for some of the drug categories, is that an area where either the federal govt or the industry as a whole can step in and develop a collective solution?
rossdavidh 6y ago
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.
- refoundable 6y ago
  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.
  - Dysseus 6y ago
    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 https://www.nature.com/articles/nrd3078
scythe 6y ago
>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.
- refoundable 6y ago
  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.
contravariant 6y ago
The current Covid-19 vaccine seems a crucial example of how important model validity can be. The mod-mRNA vaccines can apparently be created in a matter of hours and validated on animal subjects within days/weeks, yet it has taken us almost a year with extensive testing to be sure it will work and be safe. And even that is considered a record breaking time. It cannot be overstated how big an advancement in medical science it would be if we could show that all such vaccines are safe and (probably) effective.
- refoundable 6y ago
  You're right on the money. Any breakthrough that could either dramatically shorten the feedback cycle (from years to weeks), or reduce the cost of drug development by 100-1000x would unlock so much value as to completely reshape the structure of the Pharma industry. The consolidation of the industry in recent decades could be justified by the high fixed costs of drug development that made it necessary to seek greater economies of scale, but in a world where the cost of drug development drops precipitously, the pendulum could swing in the other direction, unleashing a wave of decentralization in the industry. Absent this kind of breakthrough, I expect only more intense regulatory and pricing pressures for the Pharma industry in coming years.
- eganp 6y ago
  It's a tough lift to demonstrate that all such modified-mRNA vaccines are safe and likely effective. This trial is a good validation of off-target safety, and that's a huge achievement. However, you still have on-target safety concerns (e.g. cross reactivity). Then, for each pathogen, the selected antigen expressed needs to 1. generate an antibody response and 2. provide protection from infection. Antibody titers can de-risk 1 pretty effectively. But, without human challenge trials, you're stuck waiting for nature to test 2. Even using non-human primates as the model to test infection has many pitfalls as the species barrier is often strong with infectious diseases. Human immunology is often idiosyncratic when compared with closely related primates.
Anka33 6y ago
Thanx goverment

55 points by apsec112 6y ago

forgotmypw 6y ago

Does anyone else see a blue background on this page?

refoundable 6y ago
No idea what's causing this for you. Can you say a bit more about your setup?
- cinntaile 6y ago
  Just wanted to say that I enjoyed reading the article. I liked the overall quality and that important bits have citations. I hadn't heard of your website before but I'll be sure to read more of your work in the future.
  - refoundable 6y ago
    Thank you. It takes a fair bit of time to put something like this together, so I appreciate your kind words.

deleted 6y ago

[deleted]

m463 6y ago

"Eroom's law is the observation that drug discovery is becoming slower and more expensive over time"...

refoundable 6y ago
A more accurate definition pulled from the introduction: > Eroom’s law is the observation that the cost of developing a new drug roughly doubled every nine years from 1950 through 2010. All in all, it shows a roughly 80-fold decline in the productivity of drug R&D.
- deleted 6y ago
  [deleted]

refoundable 6y ago

Author here. I interviewed Jack Scannell on the hypothesis that the man who wrote the now famous paper on Eroom's law would likely have many more insights to offer that didn't necessarily make it into print. One of the oddest things about biotech and pharma is that cures trail improvement in technology by at least a couple of decades. That's terrible news if you're a patient/consumer though maybe great news if you're a lab technician.

beloch 6y ago
The way your website handles font-size and zoom is really weird.
- titanomachy 6y ago
  I feel like there should be a named law of hacker news for this. There's sometimes more discussion about how the page doesn't work without javascript, font colors are bad, page is slow, whatever, than about the content of the article. Although in this case most people are talking about the article. Agreed though, there's some weird responsive CSS going on here that makes it impossible to resize fonts on a desktop.
  - refoundable 6y ago
    I echo both observations and urge you to name that law. Will look under the hood at the CSS.
    - jhayward 6y ago
      Thanks for looking. I use the "zoom" feature of Chrome to make fonts more readable. The CSS on this page does not permit resizing of the type - a major faux pas for accessibility. This is a fascinating article, and is even better with the conversation here added. Thanks for your efforts.
andrewjl 6y ago
The article mentions poor incentive structure around development of better disease models as an obstacle for some of the drug categories, is that an area where either the federal govt or the industry as a whole can step in and develop a collective solution?

rossdavidh 6y ago

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.

refoundable 6y ago
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.
- Dysseus 6y ago
  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 https://www.nature.com/articles/nrd3078

scythe 6y ago

>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.

refoundable 6y ago
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.

contravariant 6y ago

The current Covid-19 vaccine seems a crucial example of how important model validity can be. The mod-mRNA vaccines can apparently be created in a matter of hours and validated on animal subjects within days/weeks, yet it has taken us almost a year with extensive testing to be sure it will work and be safe. And even that is considered a record breaking time. It cannot be overstated how big an advancement in medical science it would be if we could show that all such vaccines are safe and (probably) effective.

refoundable 6y ago
You're right on the money. Any breakthrough that could either dramatically shorten the feedback cycle (from years to weeks), or reduce the cost of drug development by 100-1000x would unlock so much value as to completely reshape the structure of the Pharma industry. The consolidation of the industry in recent decades could be justified by the high fixed costs of drug development that made it necessary to seek greater economies of scale, but in a world where the cost of drug development drops precipitously, the pendulum could swing in the other direction, unleashing a wave of decentralization in the industry. Absent this kind of breakthrough, I expect only more intense regulatory and pricing pressures for the Pharma industry in coming years.
eganp 6y ago
It's a tough lift to demonstrate that all such modified-mRNA vaccines are safe and likely effective. This trial is a good validation of off-target safety, and that's a huge achievement. However, you still have on-target safety concerns (e.g. cross reactivity). Then, for each pathogen, the selected antigen expressed needs to 1. generate an antibody response and 2. provide protection from infection. Antibody titers can de-risk 1 pretty effectively. But, without human challenge trials, you're stuck waiting for nature to test 2. Even using non-human primates as the model to test infection has many pitfalls as the species barrier is often strong with infectious diseases. Human immunology is often idiosyncratic when compared with closely related primates.

Anka33 6y ago

Thanx goverment