5 ms·

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

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
  - light_hue_1 6y ago
    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 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/#:~:text=Failures%20in%20phase%20II%20testing,(15%25)%20(10) 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/ 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.
    - Dysseus 6y ago
      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.
      - refoundable 6y ago
        > 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.
- bfieidhbrjr 6y ago
  Well, are you aware that the common model of cancer (genetic) is almost certainly wrong? And that we've wasted 50+ years, and something like an infinite amount of money on it? https://www.amazon.com/Cancer-Metabolic-Disease-Management-Prevention/dp/0470584920/ref=sr_1_1?crid=28400N5LAZN0S&dchild=1&keywords=cancer+as+metabolic+disease&qid=1609179984&sprefix=cancer+as+meta%2Caps%2C-1&sr=8-1 https://www.amazon.com/Cancer-Metabolic-Disease-Management-P... https://www.amazon.com/Tripping-over-Truth-Overturning-Entrenched/dp/160358935X/ref=sr_1_1?dchild=1&keywords=tripping+over+the+truth&qid=1609180004&sr=8-1 https://www.amazon.com/Tripping-over-Truth-Overturning-Entre...
  - refoundable 6y ago
    It's worth noting that the most effectives breakthroughs against cancer in recent decades (Immunotherapy, angiogenesis-suppressing drugs) have largely been based on ideas that were first dismissed and widely ridiculed by senior scientists working on cancer research. I suspect that in another 50 years, when the war against cancer is (finally) over, we will end up with a completely different perspective on the history of cancer research than the often self-serving and propagandized perspective we have today.
    - MichaelZuo 6y ago
      Just how radical were these ideas you speak of from the accepted dogma?
      - refoundable 6y ago
        On angiogenesis, see Judah Folkman: https://www.tobinproject.org/about/judah-folkman https://www.tobinproject.org/about/judah-folkman On cancer immunotherapy, see Fran Visco's story as partially told by Daniel Sarewitz (section titled "War on Cancer"): https://www.thenewatlantis.com/publications/saving-science https://www.thenewatlantis.com/publications/saving-science
        MichaelZuo 6y ago

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
- light_hue_1 6y ago
  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 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/#:~:text=Failures%20in%20phase%20II%20testing,(15%25)%20(10) 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/ 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.
  - Dysseus 6y ago
    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.
    - refoundable 6y ago
      > 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.
bfieidhbrjr 6y ago
Well, are you aware that the common model of cancer (genetic) is almost certainly wrong? And that we've wasted 50+ years, and something like an infinite amount of money on it? https://www.amazon.com/Cancer-Metabolic-Disease-Management-Prevention/dp/0470584920/ref=sr_1_1?crid=28400N5LAZN0S&dchild=1&keywords=cancer+as+metabolic+disease&qid=1609179984&sprefix=cancer+as+meta%2Caps%2C-1&sr=8-1 https://www.amazon.com/Cancer-Metabolic-Disease-Management-P... https://www.amazon.com/Tripping-over-Truth-Overturning-Entrenched/dp/160358935X/ref=sr_1_1?dchild=1&keywords=tripping+over+the+truth&qid=1609180004&sr=8-1 https://www.amazon.com/Tripping-over-Truth-Overturning-Entre...
- refoundable 6y ago
  It's worth noting that the most effectives breakthroughs against cancer in recent decades (Immunotherapy, angiogenesis-suppressing drugs) have largely been based on ideas that were first dismissed and widely ridiculed by senior scientists working on cancer research. I suspect that in another 50 years, when the war against cancer is (finally) over, we will end up with a completely different perspective on the history of cancer research than the often self-serving and propagandized perspective we have today.
  - MichaelZuo 6y ago
    Just how radical were these ideas you speak of from the accepted dogma?
    - refoundable 6y ago
      On angiogenesis, see Judah Folkman: https://www.tobinproject.org/about/judah-folkman https://www.tobinproject.org/about/judah-folkman On cancer immunotherapy, see Fran Visco's story as partially told by Daniel Sarewitz (section titled "War on Cancer"): https://www.thenewatlantis.com/publications/saving-science https://www.thenewatlantis.com/publications/saving-science
      - MichaelZuo 6y ago