4 ms·

"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,

"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 produced. Drugs which would have worked on humans, but don't on mice, for similar reasons.

ramraj07 8y ago
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 therapeutics for almost a decade and can go on a tirade of all the shitty decisions companies seem to make in candidate identification, but fundamentally I really believe that this number won't be this low if the people making the decisions in pharma companies know what they're doing but then the CEO of gsk used to sell lipsticks so who am I to talk right?
- fredophile 8y ago
  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?
  - busyant 8y ago
    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 drug was good at ameliorating the disease in our simple models, but we also had a strong suspicion that the drug would be toxic in humans, higher animals. * A decision was made that we would determine if the drug was toxic in three different species of large animal (I think we chose some type of monkey, dogs and I don't remember). * Our "go/no-go" decision was: If the drug was NON-toxic in at least 2 of the 3 animal species, we would move to clinical (human) trials. * 6 months later, we got the results: drug was NON-toxic in 1 of the 3 species. * This looks like "no-go", right? * Wrong. Board of directors put pressure on the CEO and senior management ("We put 8 figures of our hard-earned $ into round B and you promised us clinical trials over a year ago."). * CEO folded like an accordion and got everyone to agree that we should proceed w/ Phase I trials (small n of humans tested, primarily to determine toxicity and maximum tolerated dose) despite the results of the animal studies. * Phase 1 trial starts. Everyone gets sick (maybe 10 patients) after about 5 days of taking the drug. Trial is halted. * We go back to square 1. CEO should have never folded under the pressure because it was a waste of money, time, and it put people at risk. I've only seen this once (going to trial with a risky drug), so I think it is a rare event. edit2: Ironically, this is an example of a situation where the animal-studies CORRECTLY predicted what would happen in humans.
    - dragonwriter 8y ago
      > 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.
      - busyant 8y ago
        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.")
        archgoon 8y ago
        > 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.
    - DanBC 8y ago
      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?
      - 8y ago
  - ramraj07 8y ago
    I would very much say that if the scientists and stakeholders really, really wanted to pore through the data to understand whether it might work or not, they can get some more insight from their experiments. Most antibody therapies (which form the bulk of currently explored therapies) have to be tested on modified mice models simply because of the fact that these antibodies are raised against human targets that have to be engineered into the mice. But then such artificial models make lots of complications in their interpretation which people have to spend lots of time interpreting. I've seen on several occasions from just published data that there were glaring warning signs that a potential therapy might have adverse interactions with the immune system or such, and the company would just go ahead with trials anyway.
aaavl2821 8y ago
The failure in humans of stuff that worked in mice is actually the biggest driver of the cost of drug development According to a widely cited paper on the cost of drug development [0], phase 2 has the lowest probability of succes of any stage in the funnel at 30-40%. Phase 2 is generally the first time a drugs effectiveness is studied in humans. It can cost $50-100M+ to get a drug through a phase 2 study One of the major advances in drug development in the last few years is to reduce the "translational risk", i.e. The risk that animal models and other disease models are not predictive of human outcomes. A recent study suggests that we have actually started to make some improvements in this area which is a huge step in lowering drug costs and getting more new medicines [0] https://www.nature.com/articles/nrd3078 https://www.nature.com/articles/nrd3078
ericd 8y ago
If the overlap is that small, for me it begs the question of how many drugs would work in humans, but are ruled out because they fail on mice.

ramraj07 8y ago

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 therapeutics for almost a decade and can go on a tirade of all the shitty decisions companies seem to make in candidate identification, but fundamentally I really believe that this number won't be this low if the people making the decisions in pharma companies know what they're doing but then the CEO of gsk used to sell lipsticks so who am I to talk right?

fredophile 8y ago
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?
- busyant 8y ago
  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 drug was good at ameliorating the disease in our simple models, but we also had a strong suspicion that the drug would be toxic in humans, higher animals. * A decision was made that we would determine if the drug was toxic in three different species of large animal (I think we chose some type of monkey, dogs and I don't remember). * Our "go/no-go" decision was: If the drug was NON-toxic in at least 2 of the 3 animal species, we would move to clinical (human) trials. * 6 months later, we got the results: drug was NON-toxic in 1 of the 3 species. * This looks like "no-go", right? * Wrong. Board of directors put pressure on the CEO and senior management ("We put 8 figures of our hard-earned $ into round B and you promised us clinical trials over a year ago."). * CEO folded like an accordion and got everyone to agree that we should proceed w/ Phase I trials (small n of humans tested, primarily to determine toxicity and maximum tolerated dose) despite the results of the animal studies. * Phase 1 trial starts. Everyone gets sick (maybe 10 patients) after about 5 days of taking the drug. Trial is halted. * We go back to square 1. CEO should have never folded under the pressure because it was a waste of money, time, and it put people at risk. I've only seen this once (going to trial with a risky drug), so I think it is a rare event. edit2: Ironically, this is an example of a situation where the animal-studies CORRECTLY predicted what would happen in humans.
  - dragonwriter 8y ago
    > 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.
    - busyant 8y ago
      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.")
      - archgoon 8y ago
        > 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.
  - DanBC 8y ago
    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?
    - 8y ago
- ramraj07 8y ago
  I would very much say that if the scientists and stakeholders really, really wanted to pore through the data to understand whether it might work or not, they can get some more insight from their experiments. Most antibody therapies (which form the bulk of currently explored therapies) have to be tested on modified mice models simply because of the fact that these antibodies are raised against human targets that have to be engineered into the mice. But then such artificial models make lots of complications in their interpretation which people have to spend lots of time interpreting. I've seen on several occasions from just published data that there were glaring warning signs that a potential therapy might have adverse interactions with the immune system or such, and the company would just go ahead with trials anyway.

aaavl2821 8y ago

The failure in humans of stuff that worked in mice is actually the biggest driver of the cost of drug development According to a widely cited paper on the cost of drug development [0], phase 2 has the lowest probability of succes of any stage in the funnel at 30-40%. Phase 2 is generally the first time a drugs effectiveness is studied in humans. It can cost $50-100M+ to get a drug through a phase 2 study One of the major advances in drug development in the last few years is to reduce the "translational risk", i.e. The risk that animal models and other disease models are not predictive of human outcomes. A recent study suggests that we have actually started to make some improvements in this area which is a huge step in lowering drug costs and getting more new medicines [0] https://www.nature.com/articles/nrd3078 https://www.nature.com/articles/nrd3078

ericd 8y ago

If the overlap is that small, for me it begs the question of how many drugs would work in humans, but are ruled out because they fail on mice.