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

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

#101

Post by DanBC »

busyant wrote: post #99
fredophile wrote: post #71

Earlier quoted context omitted.

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 info…

I am not the parent, but I worked at a few biotech startups. My impression is that you are _mostly_ correct (a lot of animal models for disease don't accurately reflect the analogous state in humans). However, I was privy to a situation similar to that described by the person to whom you replied. * A start-up that I worked at developed a "candidate drug" to treat a condition (I don't want to get too detailed). * The…

Imagine a similar situation but where people died: Who's corporately responsible for that decision? The company, or the individual directors? How about the NEDs?

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

#102

Post by busyant »

dragonwriter wrote: post #100
busyant wrote: post #99

Earlier quoted context omitted.

I am not the parent, but I worked at a few biotech startups. My impression is that you are _mostly_ correct (a lot of animal models for disease don't accurately reflect the analogous state in humans). However, I was privy to a situation similar to that described by the person to whom you replied. * A start-up that I worked at developed a "candidate drug" to treat a condition (I don't want to get too detailed). * The…

> CEO should have never folded under the pressure because it was a waste of money, time, and it put people at risk. At the same time, he board of directors should never have exerted the pressure, for the same reasons.

Agreed.

That company was unusual in that there always seemed to be a tension between the board and the company (distrust). And both sides (CEO and board) seemed to have a short-term view of everything (we were going to "flip" the company to a large pharma), which caused a lot of bad decisions to be made.

The other (more successful) start-ups that I worked at had a much more harmonious relationship with their boards (e.g., "We are in this together and we are here for the long-term.")

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

#103

Post by pcnix »

rajadigopula wrote: post #56
pcnix wrote: post #54

Earlier quoted context omitted.

It's not about giving confidence to people, the existing methods are part of the fundamental idea of the scientific method. Dr. Hegde's claim of body types doesn't really mean anything until there's evidence to back it up. And modern medical trials are crafted and investigated with a wide variety of statistical tools to determine the exact impact of a treatment method. Only if his claims can stand up to this rigorous…

Agree. Unfortunately, this is never going to happen. The few still practicing Ayurveda properly come from a background where they learned it from their ancestors within their family and practicing it for free and never allow commercialization of their knowledge. But they can gladly share the knowledge to people who want to learn. Food, Education and Medicine/health are the 3 things the practitioners in Indian culture…

I appreciate the honestly in this answer, and your willingness to accept how people see something you clearly seem to care about.

As for commercialization of Ayurveda, I see this as exactly what's happening now with Patanjali etc trying to cash in on people's trust in their culture without providing a proper research base for their claims.

Another reply to your comment above makes very good points about research funding, and in my experience, funding is to a large extent non partisan, and free from industry influence. There are even rules on disclosure of funding about major studies, which makes it possible to criticize them.

I only wish that Ayurveda is held to the same standards as other medicine, and passes through the fire of testing the same way all modern medicine has. It's how we know that antibiotics work, or about interactions between medicines, or about side effects and complications. It will ultimately benefit the field, and medicine as a whole.

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

#104

Post by busyant »

DanBC wrote: post #101
busyant wrote: post #99

Earlier quoted context omitted.

I am not the parent, but I worked at a few biotech startups. My impression is that you are _mostly_ correct (a lot of animal models for disease don't accurately reflect the analogous state in humans). However, I was privy to a situation similar to that described by the person to whom you replied. * A start-up that I worked at developed a "candidate drug" to treat a condition (I don't want to get too detailed). * The…

Imagine a similar situation but where people died: Who's corporately responsible for that decision? The company, or the individual directors? How about the NEDs?

> Imagine a similar situation but where people died: Who's corporately responsible for that decision?

No idea. Thankfully, all patients stopped the drug and the toxicity went away.

I remember having a company-wide meeting where they showed us a result from the Phase I trial. It was a graph of time on the x-axis and the concentration of an important molecule in each patient's bloodstream on the y-axis. Every patient had the concentration of that molecule drop to dangerously low levels after about 5 days on the drug, and I'm thinking, "Is this a surprise to anyone here?"

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

#105

Post by archgoon »

busyant wrote: post #102
dragonwriter wrote: post #100

Earlier quoted context omitted.

> CEO should have never folded under the pressure because it was a waste of money, time, and it put people at risk. At the same time, he board of directors should never have exerted the pressure, for the same reasons.

Agreed. That company was unusual in that there always seemed to be a tension between the board and the company (distrust). And both sides (CEO and board) seemed to have a short-term view of everything (we were going to "flip" the company to a large pharma), which caused a lot of bad decisions to be made. The other (more successful) start-ups that I worked at had a much more harmonious relationship with their boards (…

> seemed to have a short-term view of everything (we were going to "flip" the company to a large pharma),

> which caused a lot of bad decisions to be made.

Unfortunately, if they were trying to flip the company; then they may have made the 'right' (from the perspective of payoff) call.

I can imagine under some models, that if you are 86% confident that it won't work, and only 14% confident that it will work; then the millions wasted may have been easily justified by the potential payoff if it was in the $100 million dollar range.

Normally, we wouldn't bat an eye at such a decision; but the ugly part here is the high risk exposed to the people participating in the study :(. However, even that, a similar utilitarian calculus can be done to justify it. bleh.

Remind me not to be a Pharma CEO, it sounds like an all around unpleasant job if you aren't a complete sociopath.

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

#106

Post by najarvg »

Fascinating and very timely for me. I was privileged to sit through a talk by the head of cancer immunotherapy at our institution where he was explaining the past, present and future journey of cancer immunotherapy research and this exact topic of mouse model applicability to human subjects came up. His TLDR on this was that differences are likely due to - 1. Controlled lines of mice bred specifically to minimize confounding during pre-clinical studies 2. Immune response activation pathways differing from "in the wild" situations for actual subjects 3. The immense diversity of gut microbiota, their temporal and inherited gene signatures and impacts on drug metabolism which are incredibly hard to control for in experiments

Very nice to see an approachable post out there outlining a lot of these issues.

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

#107

Post by danieltillett »

Pfhreak wrote: post #76
danieltillett wrote: post #9

Earlier quoted context omitted.

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.

Would you let your child participate in a clinical trial if they had a disease for which there was no good treatment? Pets suffer from most of the diseases humans suffer from (cancer, heart disease, diabetes, etc) and they also have no good treatment options. We should be using these sick pets in trials to find new cures for pets and humans.

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

#109

Post by danieltillett »

opencl wrote: post #50
jz_ wrote: post #8

Earlier quoted context omitted.

People are actually very motivated to contribute to science, here's an example of research involving pets and extending their healthspan across aging: http://dogagingproject.com Phase I clinical trial: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/28374166/ Phase II is in progress. Interview with Matt Kaeberlein from the project: https://www.leafscience.org/dr-matt-kaeberlein-the-dog-aging...

This is a study of a new application of a drug that has already had very extensive trials in both humans and several species of animals that have demonstrated it to be safe (it's FDA approved for human use). I think you will find people dramatically less willing to test brand new drugs on their pets.

This question has already been asked of pet owners and when it is explained to them why most are willing to let their pets participate in trials of even new drugs.

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

#110

Post by danieltillett »

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...

I hope the person demanding using inbred mice has a compelling argument for why inbred mice are a good model of outbred humans.

Yes we would do fewer experiments since you would need more mice per experiement, but the results of those experiements would be far more robust.

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