4 ms·

Drug development has been maturing for decades. Both industry and the agency have had time to work out what animal models do and do not tell us. If you develop/

Drug development has been maturing for decades. Both industry and the agency have had time to work out what animal models do and do not tell us. If you develop/discover a molecule/drug that treats some disease, it's typically found first in single-cells, then you move into higher and higher organisms. This is the flow of development. No one thinks any mouse, even humanized mice, are surrogates for actual clinical evidence. The whole shtick is risk mitigation, it's amazing how far society has come in such a short period of time where we forget non-clinical testing is not a perfect view into how a compound will interact in a human.

mennis16 6y ago
But in certain fields this current setup seems to be failing. The large majority of clinical trials related to neuroscience fail. To the point that pharma companies are starting to defund these departments, because the hit probability is just not good enough to outweigh the costs. This is despite the fact many of our treatments are woefully inadequate and often closely related to drug discoveries made 50+ years ago. And despite the fact that the field is well funded in academia, taking up entire departments distinct from biology. Neuroscience is a hard problem no doubt, but I also think the current paradigm for how basic neuroscience research is done is way too limited, and that is impacting the viability of potential treatments that make it to clinical trial phase.
- ethbro 6y ago
  > I also think the current paradigm for how basic neuroscience research is done is way too limited, and that is impacting the viability of potential treatments that make it to clinical trial phase. Our current paradigm is optimized to avoid injuring humans at all costs, including to the extent that it diminishes the chance of success. By advocating for a different model, we're stating "Avoiding injuring humans in drug discovery is not our primary concern." Maybe that's worth it in a broader calculation, but let's be honest about what we're talking about. Pharma companies and regulatory bodies don't put in place billion+ dollar trial hoops on a whim: they do so to avoid permanently injuring or killing people with some pretty horrific side effects, to the extent we can.
  - mennis16 6y ago
    That's not true at all. The way the data is analyzed could be done differently for example- there are some cases where previous clinical trials were brought back up as possibly helping a subset of the individuals, but got thrown away because of p-values. When our disease labels are so bad this is the type of thing that needs to be especially carefully considered. But also I was talking about basic neuroscience. The pharma companies don't just magically start a clinical trial, as you said. They base the clinical trials on previous results from academia and their own basic research labs. Which mostly doesn't involve humans at all. Perhaps those labs are not putting forward the best candidates, or not doing as good a job as they could be at eliminating candidates.
  - jcims 6y ago
    >Our current paradigm is optimized to avoid injuring humans at all costs, including to the extent that it diminishes the chance of success. I would characterize it as more avoiding the liability of injury to humans than avoiding injury overall (edit: and by liability i'm not just talking legal liability, there are also emotional consequences a person would experience if someone dies or is gravely injured as part of their medical research). A family member died of cancer this year. Nobody is liable for her 'injury' because there's no evidence it wasn't a natural occurrence and standard of care was followed in her treatment. However, a number of plausibly beneficial alternatives or adjuncts to that standard were in phase 3 trials that either her doctor flat out refused to consider or that she was ineligible for...not due to concerns of clinical efficacy of the treatment, but due to prior treatments that could have smeared the signal in the results (this is particularly true for immunotherapy trials). It's a medical version of the trolly problem and from what I can see and definitely in our experience doctors choose to ride the rails they were set on. I don't blame them either. With the current climate in medicine a wrong move could end their career and possibly prevent them from helping those in the future. It's an extremely tricky situation and I empathize with those that are faced with these dilemmas every day at the office. I just don't buy the story that changing our current approach is somehow de-prioritizing injury avoidance.
  - throwaway0a5e 6y ago
    Your comment reminds me of the recent Dilbert strips where everyone is acting like the main character doesn't care about safety because he didn't state the implicit assumption that safety matters and someone looking for cheap virtue points noticed and said "you didn't mention safety, why don't you care about safety" even though he obviously cares as much as anyone else. Nobody in this entire comment section that I have seen so far is advocating for harming more people more frequently in the name of progress. Just because people are asking "are there any other ways of testing drugs" and the current testing system cares about safety does not mean that these people want to abandon safety in order to more cheaply test drugs. Maybe we can find some other way to test drugs that is cheaper per useful drug than the current system and equivalent or better in terms of safety to humans.

mennis16 6y ago

But in certain fields this current setup seems to be failing. The large majority of clinical trials related to neuroscience fail. To the point that pharma companies are starting to defund these departments, because the hit probability is just not good enough to outweigh the costs. This is despite the fact many of our treatments are woefully inadequate and often closely related to drug discoveries made 50+ years ago. And despite the fact that the field is well funded in academia, taking up entire departments distinct from biology. Neuroscience is a hard problem no doubt, but I also think the current paradigm for how basic neuroscience research is done is way too limited, and that is impacting the viability of potential treatments that make it to clinical trial phase.

ethbro 6y ago
> I also think the current paradigm for how basic neuroscience research is done is way too limited, and that is impacting the viability of potential treatments that make it to clinical trial phase. Our current paradigm is optimized to avoid injuring humans at all costs, including to the extent that it diminishes the chance of success. By advocating for a different model, we're stating "Avoiding injuring humans in drug discovery is not our primary concern." Maybe that's worth it in a broader calculation, but let's be honest about what we're talking about. Pharma companies and regulatory bodies don't put in place billion+ dollar trial hoops on a whim: they do so to avoid permanently injuring or killing people with some pretty horrific side effects, to the extent we can.
- mennis16 6y ago
  That's not true at all. The way the data is analyzed could be done differently for example- there are some cases where previous clinical trials were brought back up as possibly helping a subset of the individuals, but got thrown away because of p-values. When our disease labels are so bad this is the type of thing that needs to be especially carefully considered. But also I was talking about basic neuroscience. The pharma companies don't just magically start a clinical trial, as you said. They base the clinical trials on previous results from academia and their own basic research labs. Which mostly doesn't involve humans at all. Perhaps those labs are not putting forward the best candidates, or not doing as good a job as they could be at eliminating candidates.
- jcims 6y ago
  >Our current paradigm is optimized to avoid injuring humans at all costs, including to the extent that it diminishes the chance of success. I would characterize it as more avoiding the liability of injury to humans than avoiding injury overall (edit: and by liability i'm not just talking legal liability, there are also emotional consequences a person would experience if someone dies or is gravely injured as part of their medical research). A family member died of cancer this year. Nobody is liable for her 'injury' because there's no evidence it wasn't a natural occurrence and standard of care was followed in her treatment. However, a number of plausibly beneficial alternatives or adjuncts to that standard were in phase 3 trials that either her doctor flat out refused to consider or that she was ineligible for...not due to concerns of clinical efficacy of the treatment, but due to prior treatments that could have smeared the signal in the results (this is particularly true for immunotherapy trials). It's a medical version of the trolly problem and from what I can see and definitely in our experience doctors choose to ride the rails they were set on. I don't blame them either. With the current climate in medicine a wrong move could end their career and possibly prevent them from helping those in the future. It's an extremely tricky situation and I empathize with those that are faced with these dilemmas every day at the office. I just don't buy the story that changing our current approach is somehow de-prioritizing injury avoidance.
- throwaway0a5e 6y ago
  Your comment reminds me of the recent Dilbert strips where everyone is acting like the main character doesn't care about safety because he didn't state the implicit assumption that safety matters and someone looking for cheap virtue points noticed and said "you didn't mention safety, why don't you care about safety" even though he obviously cares as much as anyone else. Nobody in this entire comment section that I have seen so far is advocating for harming more people more frequently in the name of progress. Just because people are asking "are there any other ways of testing drugs" and the current testing system cares about safety does not mean that these people want to abandon safety in order to more cheaply test drugs. Maybe we can find some other way to test drugs that is cheaper per useful drug than the current system and equivalent or better in terms of safety to humans.