5 ms·

The authors argue for using better predictive models to screen drugs at an early stage, because too many drugs are failing at costly clinical trials. In my opi

The authors argue for using better predictive models to screen drugs at an early stage, because too many drugs are failing at costly clinical trials. In my opinion we already know the best predictive model to use, but we choose not to use it. When Jenner developed the first vaccine back around 1800 he didn't use any petri dishes or mathematical models: he just found some nearby children and tested his theory directly. Now you may find this ethically repulsive but from a consequentialist point of view it was the right thing to do at the time. This line of research saved hundreds of millions of lives. I say we have gone too far in the other direction. The problem with failed costly clinical trials is not the failure per se but the cost: in money spent, time, reputation, commercial return, legal consequences, etc. And the hidden cost of how long the whole process takes even if successful. Take the field of monoclonal antibodies. We now have almost off-the-shelf technology to develop drugs that specifically block certain biological mechanisms. But it still takes 10-15 expensive years to progress through different lab and animal models, then healthy humans, before clinical trials on actual patients. Instead we should reduce the cost of human trials: have a network of terminally ill volunteers to test mabs at an early stage. Fail fast to move fast. Use the money saved to offer defined compensation when things go wrong. The drugs that we really want to find are the ones with an obvious effect on real patients. This process would find those drugs much faster, and save lives overall.

refurb 11y ago
I get where you're coming from, but I think your idea moves too far in the opposite direction. Vaccines are somewhat different as "drugs". They are typically inactivated virus or bacteria (or fragments of them), so the safety risk is somewhat muted in the sense you aren't introducing something completely new into the body. The risk is still there, but not as much as a completely new molecule. If you were to test new drugs on terminally ill patients and the patient died, was it the drug? Or did they die form their disease? Sometimes you can, often you can't. When you do clinical trials you're trying to eliminate any many variables as possible by running the trial on a relatively homogeneous population. That's why they do phase 1 with healthy volunteers. The other challenge is that when human testing goes wrong, it can go horribly wrong. Check out the clinical trial of the FAAH Bial compound where people died. Also, TGN1412.
- tominous 11y ago
  If you treat a terminally ill patient and they die, then you can still learn something. Maybe there was no effect at all on the target illness, e.g. the cancer spread and grew anyway. Maybe there was a large effect but the side effects were too severe, in which case you can investigate strategies for mitigation. TGN1412 is a good example. This drug turned out to provoke the immune system in an extreme way. What if it had been tested first on cancer patients and, even with the life-threatening side effects, it worked as a cancer immunotherapy? Then we would be able to work on dosing or mitigation. Instead, the company folded, the research was abandoned and we'll probably never know. And further, it's a cold calculation but instead of having healthy lives ruined you would have terminally ill patients die slightly sooner.
  - 467568985476 11y ago
    Frankly I think this is a ridiculous, inhumane, and fundamentally ignorant point of view. Ridiculous - The idea of testing drugs with the hope that they magically treat something completely unexpected and without any theoretical framework supporting it. Inhumane - Terminally ill people could hardly consent en masse to such a program. I suppose there is a utopic idea here, but you might as well wish everyone were healthy forever. Fundamentally ignorant - The previous comment explained why terminally ill patients with many different medical problems would make poor subjects for a study that ostensibly informs medicine applied to generally healthy people.
    - tominous 11y ago
      Let's cover these one by one. "Ridiculous": the whole point of the OP is that we don't have good predictive models for what treatments will be effective. We have hunches and theories but it is currently too costly to go through the whole process to test them all. One approach would be develop better models, but I'm suggesting another approach would be to reduce the cost of testing them in the real target. "Inhumane": well that's the ethical question. Some countries compell vaccination because of the societal benefit. I'm not even proposing compulsion. "Fundamentally ignorant": in the end medicine is needed to treat sick people, not healthy people. The OP makes the point that sometimes a biased, representative sample is better than an unbiased, unrepresentative sample.
pinaceae 11y ago
Only works for treatments that go after the terminally ill, who already have massive issues. What if it is a vaccine against cancer (such as the HPV one)? You think a sane parent would offer their healthy child for a drug trial? You'd need the fucking Nazis to accomplish this (they did, see Mengele et al). "ethically repulsive but from a consequentialist point of view" or just plain crazy.
- tominous 11y ago
  You'll note I'm proposing this accelerated approach only for terminally ill volunteers, not healthy children. I haven't edited my comment. Strangely enough, we already test vaccines and other drugs on healthy volunteers.
  - blaurenceclark 11y ago
    Yup! And they get paid (sometimes well) to be vaccine trial participants I believe

refurb 11y ago

I get where you're coming from, but I think your idea moves too far in the opposite direction. Vaccines are somewhat different as "drugs". They are typically inactivated virus or bacteria (or fragments of them), so the safety risk is somewhat muted in the sense you aren't introducing something completely new into the body. The risk is still there, but not as much as a completely new molecule. If you were to test new drugs on terminally ill patients and the patient died, was it the drug? Or did they die form their disease? Sometimes you can, often you can't. When you do clinical trials you're trying to eliminate any many variables as possible by running the trial on a relatively homogeneous population. That's why they do phase 1 with healthy volunteers. The other challenge is that when human testing goes wrong, it can go horribly wrong. Check out the clinical trial of the FAAH Bial compound where people died. Also, TGN1412.

tominous 11y ago
If you treat a terminally ill patient and they die, then you can still learn something. Maybe there was no effect at all on the target illness, e.g. the cancer spread and grew anyway. Maybe there was a large effect but the side effects were too severe, in which case you can investigate strategies for mitigation. TGN1412 is a good example. This drug turned out to provoke the immune system in an extreme way. What if it had been tested first on cancer patients and, even with the life-threatening side effects, it worked as a cancer immunotherapy? Then we would be able to work on dosing or mitigation. Instead, the company folded, the research was abandoned and we'll probably never know. And further, it's a cold calculation but instead of having healthy lives ruined you would have terminally ill patients die slightly sooner.
- 467568985476 11y ago
  Frankly I think this is a ridiculous, inhumane, and fundamentally ignorant point of view. Ridiculous - The idea of testing drugs with the hope that they magically treat something completely unexpected and without any theoretical framework supporting it. Inhumane - Terminally ill people could hardly consent en masse to such a program. I suppose there is a utopic idea here, but you might as well wish everyone were healthy forever. Fundamentally ignorant - The previous comment explained why terminally ill patients with many different medical problems would make poor subjects for a study that ostensibly informs medicine applied to generally healthy people.
  - tominous 11y ago
    Let's cover these one by one. "Ridiculous": the whole point of the OP is that we don't have good predictive models for what treatments will be effective. We have hunches and theories but it is currently too costly to go through the whole process to test them all. One approach would be develop better models, but I'm suggesting another approach would be to reduce the cost of testing them in the real target. "Inhumane": well that's the ethical question. Some countries compell vaccination because of the societal benefit. I'm not even proposing compulsion. "Fundamentally ignorant": in the end medicine is needed to treat sick people, not healthy people. The OP makes the point that sometimes a biased, representative sample is better than an unbiased, unrepresentative sample.

pinaceae 11y ago

Only works for treatments that go after the terminally ill, who already have massive issues. What if it is a vaccine against cancer (such as the HPV one)? You think a sane parent would offer their healthy child for a drug trial? You'd need the fucking Nazis to accomplish this (they did, see Mengele et al). "ethically repulsive but from a consequentialist point of view" or just plain crazy.

tominous 11y ago
You'll note I'm proposing this accelerated approach only for terminally ill volunteers, not healthy children. I haven't edited my comment. Strangely enough, we already test vaccines and other drugs on healthy volunteers.
- blaurenceclark 11y ago
  Yup! And they get paid (sometimes well) to be vaccine trial participants I believe