5 ms·

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 th

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.
refoundable 6y ago
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.
- tehjoker 6y ago
  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.
  - refoundable 6y ago
    I see no reason why we can't do both. We obviously need better drugs for the diseases we haven't yet cured, and we need cheaper drugs for the diseases we've already cured. The two are related yet distinct problems. Incidentally, Scannell wrote one of the best teardowns of how drug pricing actually works: https://www.forbes.com/sites/matthewherper/2015/10/13/four-reasons-drugs-are-expensive-of-which-two-are-false/ https://www.forbes.com/sites/matthewherper/2015/10/13/four-r...
- Dysseus 6y ago
  First, really appreciate the engagement here. This is a hugely important problem and this interview and your presentation of it is a great contribution. I think one of the things that gets lost when we talk about Eroom's law is that the original data points were established before congress passed the Kefauver-Harris amendments in 1962 which set standards for clinical trials, iNDA process, and basically required that drugs show efficacy before they could be marketed. An important part of those amendments is they made the drug companies go back and review the 4,000 drugs already on the market and provide evidence on their efficacy. It took FDA a long time to work through that backlog, but when they did: "In January 1968, the Drug Efficacy Study panels finally reported their conclusions to the FDA. They had reviewed over 16,500 therapeutic claims for 4,000 pre-1962 drugs. Only 434, about 12 percent of those examined, delivered on all their promised claims. Seven hundred and sixty-nine were marked as 'ineffective'" [0]. I bring that up to say two things: 1) Our baseline in examining Eroom's law is a bit skewed because standards have been going up since the graph begins. 2) We should be careful in how we change those standards. Many of them were bought with patients lives. I need to go now, but I do want to address your comment on pricing later. Thank you again. Really great work. [0] Pharma - Gerald Posner - Pg 224. https://www.amazon.com/Pharma-Greed-Lies-Poisoning-America-ebook/dp/B07THB8GRL/ref=tmm_kin_swatch_0?_encoding=UTF8&qid=1609177152&sr=8-1 https://www.amazon.com/Pharma-Greed-Lies-Poisoning-America-e...

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.

refoundable 6y ago

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.

tehjoker 6y ago
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.
- refoundable 6y ago
  I see no reason why we can't do both. We obviously need better drugs for the diseases we haven't yet cured, and we need cheaper drugs for the diseases we've already cured. The two are related yet distinct problems. Incidentally, Scannell wrote one of the best teardowns of how drug pricing actually works: https://www.forbes.com/sites/matthewherper/2015/10/13/four-reasons-drugs-are-expensive-of-which-two-are-false/ https://www.forbes.com/sites/matthewherper/2015/10/13/four-r...
Dysseus 6y ago
First, really appreciate the engagement here. This is a hugely important problem and this interview and your presentation of it is a great contribution. I think one of the things that gets lost when we talk about Eroom's law is that the original data points were established before congress passed the Kefauver-Harris amendments in 1962 which set standards for clinical trials, iNDA process, and basically required that drugs show efficacy before they could be marketed. An important part of those amendments is they made the drug companies go back and review the 4,000 drugs already on the market and provide evidence on their efficacy. It took FDA a long time to work through that backlog, but when they did: "In January 1968, the Drug Efficacy Study panels finally reported their conclusions to the FDA. They had reviewed over 16,500 therapeutic claims for 4,000 pre-1962 drugs. Only 434, about 12 percent of those examined, delivered on all their promised claims. Seven hundred and sixty-nine were marked as 'ineffective'" [0]. I bring that up to say two things: 1) Our baseline in examining Eroom's law is a bit skewed because standards have been going up since the graph begins. 2) We should be careful in how we change those standards. Many of them were bought with patients lives. I need to go now, but I do want to address your comment on pricing later. Thank you again. Really great work. [0] Pharma - Gerald Posner - Pg 224. https://www.amazon.com/Pharma-Greed-Lies-Poisoning-America-ebook/dp/B07THB8GRL/ref=tmm_kin_swatch_0?_encoding=UTF8&qid=1609177152&sr=8-1 https://www.amazon.com/Pharma-Greed-Lies-Poisoning-America-e...