Why Drugs That Work in Mice Don't Work in Humans • Hacker News Board

Re: Why Drugs That Work in Mice Don't Work in Humans

#71

Post by fredophile » Thu, Feb 28, 2019, 4:27 PM UTC

ramraj07 wrote: post #60

dalbasal wrote: post #49

"Only 14% of drugs that are tested on humans succeed in demonstrating effectiveness[1], and all of these are drugs that have been found efficacious in animals, so successful animal studies are very far from a guarantee by themselves." Regardless of the reason, this seems fine/workable. Animal studies are a step in the funnel. I assume the step from petri dish to mouse is similar. I wonder how many false negatives get…

14% is bad when you consider that the NEXT step after preclinical experiments is basically clinical trials (and Phase I is not to test efficacy ) which effectively costs several hundred millions of dollars or more. And the pharmas would just add the cost of 86% failed trials to the other meds that do pass, so they effectively pass the cost of their bad decisions to us. I worked in a lab that studies antibody therapeu…

I've always assumed that the reason for the low rate of success at that stage was just a result of things that work on rats not working on humans. Your post is suggesting that there is some evidence available before testing on people that would help increase this rate but gets ignored. I haven't seen anyone express this view before and would like to learn more about it. Would you please elaborate on what kind of information isn't being used for decision making but should be?

Re: Why Drugs That Work in Mice Don't Work in Humans

#72

Post by aaavl2821 » Thu, Feb 28, 2019, 4:43 PM UTC

syntaxing wrote: post #53

I wonder if it's possible to use machine learning to speed up this process. Rather than doing computational biology, can we use a hybrid system? For instance, can we test this on mice and then feed some sort of parameter into a model to see the probability it working on humans rather than testing it directly on humans. I'm sure this won't be a perfect model but I wonder if it can raise the 14% to 20% while using less…

ML (or anything really) that could predict which molecules would work in humans without testing them in humans would probably be on of the most important advances in medicine ever, and would massively lower drug costs and open up new areas for drug research

Phase 2 failure -- ie stuff failing in humans after working in mice -- is the biggest cost driver in drug dev. You spend $50-100M+ to get there and 35% of things fail. If you could eliminate you'd cut a massive chunk of the cost and risk of drug dev

However I don't think ML is the thing to study if you want to create ML to predict whether drugs will work in people. There is not enough data about how the human body works to develop a good model. Better to work in biology to develop good models of disease, or in developing tools to better measure the molecular biology of the living human body. It's unclear if predicting drug effectiveness with ML will be possible in our generation

For more near term applications of ML in drug discovery and development see here: https://www.getrevue.co/profile/nathanbenaich/issues/6-impac...

Re: Why Drugs That Work in Mice Don't Work in Humans

#73

Post by moosey » Thu, Feb 28, 2019, 4:56 PM UTC

klmr wrote: post #57

jimmy1 wrote: post #51

We discard aborted fetuses because they are "clump of cells" and Planned Parenthood already sells off their body parts, why not take the next logical leap and test in utero of a woman that doesn't want their baby? (It's a serious question, regardless of the fact that society has reached the point where we do not apply intristic value to a baby inside the womb, only outside the womb and "wanted", biologically speaking…

> society has reached the point where we do not apply intristic value to a baby inside the womb, only outside the womb This is completely false, and a typical mischaracterisation of abortion by anti-choice advocates. If what you said were true, abortion would generally be permitted up until the moment of birth. Yet virtually nobody wants that. Abortions are performed in extremely early stages of gestation. Where exac…

> Abortions are performed in extremely early stages of gestation

Typically, yes. Later abortions are necessary though as well, and when they happen typically it is to a person who wants to keep a child.

My wife and I had a son that failed to develop heart chambers, noticed at a 24 week check up. We had two options: He was likely to die in utero, but if we did not terminate, there was a possibility he could survive to birth, only to immediately die a painful death. We opted to not increase human suffering with a procedure that is no longer available in the state of Ohio, due to the heartbeat bill. I might also add that women have lost their ability to have children due to that bill, it's god awful.

Ultimately, I think we should accept that abortion is complicated, and get these pointless moralizations out of the law books.

Re: Why Drugs That Work in Mice Don't Work in Humans

#74

Post by sshumaker » Thu, Feb 28, 2019, 5:00 PM UTC

jimmy1 wrote: post #62

klmr wrote: post #57

Earlier quoted context omitted.

> society has reached the point where we do not apply intristic value to a baby inside the womb, only outside the womb This is completely false, and a typical mischaracterisation of abortion by anti-choice advocates. If what you said were true, abortion would generally be permitted up until the moment of birth. Yet virtually nobody wants that. Abortions are performed in extremely early stages of gestation. Where exac…

> and a typical mischaracterisation of abortion by anti-choice advocates. Be that as it may, whatever the "anti-choice" advocates are doing (I certainly don't know) this is my own opinion using my own reasoning and conclusions. You either value life or you don't. I don't subscribe to the unscientific viewpoint that at some magical point after gestation, a unique human biological life somehow went from being not valua…

Look up the statistics. Majority of abortions are before 21 weeks (only 1.3% after). The vast majority of late-term abortions are for medical reasons, such as non-viability of fetus or endangerment of mother. The point of the law is to prevent the government from interfering in a doctor’s ability to provide medical care. Northam made a gaffe when speaking, but he is an actual doctor who has witnessed the actual terrible tragedies that can happen during pregnancy, as opposed to armchair quarterbacks who are jumping up and down to get their religious worldviews validated by law.

Re: Why Drugs That Work in Mice Don't Work in Humans

#75

Post by moosey » Thu, Feb 28, 2019, 5:01 PM UTC

jimmy1 wrote: post #62

klmr wrote: post #57

Earlier quoted context omitted.

> society has reached the point where we do not apply intristic value to a baby inside the womb, only outside the womb This is completely false, and a typical mischaracterisation of abortion by anti-choice advocates. If what you said were true, abortion would generally be permitted up until the moment of birth. Yet virtually nobody wants that. Abortions are performed in extremely early stages of gestation. Where exac…

> and a typical mischaracterisation of abortion by anti-choice advocates. Be that as it may, whatever the "anti-choice" advocates are doing (I certainly don't know) this is my own opinion using my own reasoning and conclusions. You either value life or you don't. I don't subscribe to the unscientific viewpoint that at some magical point after gestation, a unique human biological life somehow went from being not valua…

> After 20 weeks of gestation

Doctors that do optional abortions at this point are, at worst, rare. At best, they'll lose their license.

> You either value life or you don't.

We are at an imbalance point on this planet, and we have overpopulated. Reducing the number of people being born in high carbon usage areas is probably one of the best things that we can do to protect life.

Re: Why Drugs That Work in Mice Don't Work in Humans

#76

Post by Pfhreak » Thu, Feb 28, 2019, 5:18 PM UTC

danieltillett wrote: post #9

saagarjha wrote: post #6

Earlier quoted context omitted.

Good luck getting people to allow their pets being used for research!

People are really keen to allow their pets to be used in research as long as they understand the importance. Pets are a massive resource that is just being wasted.

I find this attitude astonishing. My pets are members of my family, and I'd generally rail against experimenting on my family.

Re: Why Drugs That Work in Mice Don't Work in Humans

#77

Post by zinclozenge » Thu, Feb 28, 2019, 5:22 PM UTC

syntaxing wrote: post #53

I wonder if it's possible to use machine learning to speed up this process. Rather than doing computational biology, can we use a hybrid system? For instance, can we test this on mice and then feed some sort of parameter into a model to see the probability it working on humans rather than testing it directly on humans. I'm sure this won't be a perfect model but I wonder if it can raise the 14% to 20% while using less…

The short answer is "probably". The use of AI in drug design is only just now starting, we'll see the results in about 10 years. I optimistically expect AI to be able to shave off ~2-3 years of the drug lifecycle.

edit: but it won't do much to optimize P2 trial success specifically, it'll simply help iterate substantially faster in the pre-P2 trial phases.

Re: Why Drugs That Work in Mice Don't Work in Humans

#78

Post by ams6110 » Thu, Feb 28, 2019, 5:24 PM UTC

moosey wrote: post #73

klmr wrote: post #57

Earlier quoted context omitted.

> society has reached the point where we do not apply intristic value to a baby inside the womb, only outside the womb This is completely false, and a typical mischaracterisation of abortion by anti-choice advocates. If what you said were true, abortion would generally be permitted up until the moment of birth. Yet virtually nobody wants that. Abortions are performed in extremely early stages of gestation. Where exac…

> Abortions are performed in extremely early stages of gestation Typically, yes. Later abortions are necessary though as well, and when they happen typically it is to a person who wants to keep a child. My wife and I had a son that failed to develop heart chambers, noticed at a 24 week check up. We had two options: He was likely to die in utero, but if we did not terminate, there was a possibility he could survive to…

A few (but not many) people would be against aborting a nonviable fetus. Fortunately these cases are rare, and IMO medically necessary abortion should not be conflated with "abortion on demand" in policy/laws.

I'm sorry for you and your wife that you had to go through that, it must have been exceedingly difficult for you.

Re: Why Drugs That Work in Mice Don't Work in Humans

#79

Post by ghostbrainalpha » Thu, Feb 28, 2019, 5:26 PM UTC

JulianMorrison wrote: post #55

jimmy1 wrote: post #51

We discard aborted fetuses because they are "clump of cells" and Planned Parenthood already sells off their body parts, why not take the next logical leap and test in utero of a woman that doesn't want their baby? (It's a serious question, regardless of the fact that society has reached the point where we do not apply intristic value to a baby inside the womb, only outside the womb and "wanted", biologically speaking…

Aside from the obvious reasons why testing on a fetus is more ethically fraught than just ending it, it's also stupidly dangerous to test things in a live human, and a mother counts as a live human.

Ya, obviously that person only wants to talk about abortion.

That joke/idea was only tangentially connected to the topic of this article.

Re: Why Drugs That Work in Mice Don't Work in Humans

#80

Post by ennisthemennis » Thu, Feb 28, 2019, 5:33 PM UTC

apathy wrote: post #52

danieltillett wrote: post #24

Earlier quoted context omitted.

Yes I know why inbred bred mice are used, but the end result is often a more accurate result that is meaningless. Use more outbred mice and do fewer experiements.

Good luck in study section, especially with mouse specialists. I hope you have a mighty compelling argument for why a random sample of (say) house mice is going to be free of unmeasured confounding effects...

Humans have a shit ton of unmeasured confounding effects though. Which means there is an even bigger leap between inbred mice and human studies. Not saying we should abandon the current way of doing things, but a little more diversity in funded research might be a good thing, because there are some modes of failure right now.

A way to evaluate drug efficacy that relies less on comparisons of large groups would be a big step, because there are a lot of disorders that are probably multiple mechanisms manifesting in similar ways

Ultimately there is always going to be some trade-off between making a rigorous statement and a generalizeable one, especially because biology seems to have some pretty messy abstractions. As collecting and analyzing large amounts of data becomes more feasible, I don't see why there shouldn't be some efforts to consider genetic (or environmental) heterogeneity in animal models. Ideally I think it'd be cool to approach any given question with parallel methods that can try to address how the hypothesis holds up both in more narrow but well controlled situations, and in the "wild"