5 ms·

This comment makes no sense. Why would anyone make a drug if the current prevalent treatment was as good as a functional cure? What do lorbrena and keytruda h

This comment makes no sense. Why would anyone make a drug if the current prevalent treatment was as good as a functional cure? What do lorbrena and keytruda have to do with the rate of failures being constant?

db48x 3mo ago
These are examples of ambitious drugs that wouldn’t have been attempted even a few decades earlier. But technology improved and the money was there so they tried anyway, and found success. But for any 3 successes there are still 27 failures because those 27 were equally ambitious.
- junofan 3mo ago
  Feels like a just-so story. How to quantify “ambitious”? If the goal were flight, would jumping off cliffs with wings like birds be “ambitious”? The most parsimonious explanation is either our models or methods (or both) are garbage. Something’s missing. The failure rate is insane, and writing it off as ambition or “biology is hard” rather than digging in does us no favors.
  - s1artibartfast 3mo ago
    I don't know who you or the article are directing that criticism at. Both models and methods are challenging. Biology is hard. Who isn't digging in exactly? Pharmaceuticals are more than a two trillion dollar market with Millions of scientists and engineers and doctors working diligently to refine the process. There's tens of billions of dollars to gain for any company that comes up with even minor improvements to success rate.
  - db48x 3mo ago
    You’ve misunderstood. Nobody here has said that we shouldn’t try to improve the success rate, only that improving the success rate will make people try harder problems which worsens the success rate. If this is true, it just means that any effort you make to improve the success rate really has the effect of improving the quality of our medicines rather than reducing the failure rate. Keep in mind that we’re talking about the success rate of the last step in the process: human trials. For every human trial there were millions of drug candidates that were considered and rejected. Tens of thousands of those candidates were actually synthesized and tested in animal models or in cell cultures. In the 80s these numbers were all lower. Back then only thousands of candidates would be considered, and only hundreds would be synthesized for actual testing. Worse, for every candidate that gets to the human trial stage there were multiple projects that rejected all of their candidates and were discontinued. The numbers here are pretty vague, but past surveys have found that the number of failures at this stage is really high too, maybe as high as 90%. Pharma companies are hardly unaware of this problem. They regularly spend years (even decades) and hundreds of millions of dollars on drug projects that never reach human trials. They spend even more on the ones that reach human trials and then fail. As a result they have spent billions on new methods, new systems, new techniques, etc, all intended to reduce that risk. It appears that all they have managed to do is keep pace with the increasing difficulty of drug development. I don’t necessarily agree that this is inevitable, but it is understandable. > The most parsimonious explanation is either our models or methods (or both) are garbage. I disagree with that. In spite of the difficulties we have managed to get around 50 new drugs approved every year for the last several decades. Sometimes more, sometimes less, of course, but as far as I know there’s been no obvious trend upwards or downwards. That doesn’t seem like garbage to me. > If the goal were flight, would jumping off cliffs with wings like birds be “ambitious”? Not any more, no, but it was quite ambitious back in the 1890s. Back then there was a single scholarly study on the lift generated by wings, and it was completely wrong. The Wright brothers built their own wind tunnel and ran their own tests to get reliable data to base the Flyer’s wings on.
- deleted 3mo ago
  [deleted]
s1artibartfast 3mo ago
Keytruda revenue is 30+ billion per year. If your new drug performs 1% better than Keytruda, that revenue becomes yours. If your drug perfroms 1% worse, you become a failure in the statistics.
- bonsai_spool 3mo ago
  That isn’t how a rational person would pursue this - it costs $1B to make a drug start to finish, and there’s no reason to believe your new mechanism will work. If you’re talking about copycat mechanisms, that is fine but we’re still left discussing successes when OP is about failures
  - s1artibartfast 3mo ago
    Why isnt it rational? You spend the 1 billion for a ticket to win 30 billion/yr for the next several years. Is it rational to spend 1$ to make $100 10% of the time? A 99% failure rate would be break even.
    - bonsai_spool 3mo ago
      > Why isnt it rational? You can spend that $1B to win a new category or that same money to maybe be non-inferior to Keytruda, but maybe fail. I think copycat design does happen, but I mostly notice it when drugs are being developed simultaneously at different firms. Perhaps it happens more beyond this, I'm unsure. Otherwise, it makes more sense to try to find an indication where you are approved and have no competition.
      - s1artibartfast 3mo ago
        I don't think you are looking at this from the rational economic perspective. I'm not talking about biosimilars or strict copycats. Completely novel indications are a tiny portion of Pharma development. Lucrative and technologically viable untreated indications are few and far between. Meanwhile, you have huge proven markets for treatments that impact millions of people with corresponding Revenue. If you are skeptical, you can simply go look at the development Pipelines for the top 10 pharmaceutical Giants and see how many of their new programs are for indications with existing treatments versus orphan. In recent years, approximately one-third of all novel new drugs approved annually by the FDA have carried a Breakthrough Therapy Designation. This corresponds to drugs that claim a substantial improvement over the standard of care for their target disease.
evandijk70 3mo ago
Lots of reasons. The new drug could be cheaper to manufacture, fewer side effects, a full cure in stead of a functional cure.
- bonsai_spool 3mo ago
  Cost of manufacture is not a meaningful driver of pricing outside the biological How will your clinical trial of the ostensible full cure work if standard of care is curing people?
  - evandijk70 3mo ago
    A full cure would probably have less side-effects, since a functional cure means a life-long dependence on drugs.
inglor_cz 3mo ago
"Why would anyone make a drug if the current prevalent treatment was as good as a functional cure?" I am not sure whether you ask for economic why, or an overall why. The overall why seems easier to explain: a. The new drug may be cheaper. b. The new drug may be safer. (e.g. no risk of anaphylaxis etc.) c. The new drug may not need cold storage (huge problem outside the First World). d. The new drug may have other properties that the original does not have (e.g. being taken once a day instead of four times a day, not requiring people to stay off specific food etc.) e. The side effects (such as vomiting) may be lower. In general, it is always better to have alternatives in medicine.
- bonsai_spool 3mo ago
  This is very facile thinking - are there any examples of a-e in the real world (namely, a brand new drug program was spun up to exploit a-e) ? I think not, which is why I asked the question.
  - inglor_cz 3mo ago
    IIRC there are serious attempts at "vaccination plasters", which would solve the cold storage problems of classical vaccines. Some really bad infections survive in reservoirs far from the closest hospital with reliable electricity. And frankly your comment about "facile thinking" is totally unwelcome. Have you seen someone vomiting their guts out after chemo? That is torture. Oncology is one field where every less punishing treatment would be useful. Some patients have to be taken off otherwise life-saving treatments because they cannot tolerate them. That is true even with well-treatable cancers such as Hodgkins, which 90+ per cent of patients survive.
    - bonsai_spool 3mo ago
      I have seen these people, but we are speaking about drug companies making new drugs. I am not aware of an example of a new chemotherapeutic developed to reduce the side effects of a previous agent - that seems even less reasonable from an ROI perspective since we have good agents to control chemo-associated nausea. (edit) If a new agent happens to cause fewer side effects, that is welcome. But how would you justify the risk of the new agent not working at all? The search for different formulations of an active agent seems a little unrelated (sibling comment to yours) but I concede that I didn't exclude that in my earlier argument. -- My point is that several posters here are giving arguments from first principles ('yes of course we would want to keep trying to make more medications because more options is better than fewer options') but not engaging with the enormous cost such a rationale would entail.

db48x 3mo ago

These are examples of ambitious drugs that wouldn’t have been attempted even a few decades earlier. But technology improved and the money was there so they tried anyway, and found success. But for any 3 successes there are still 27 failures because those 27 were equally ambitious.

junofan 3mo ago
Feels like a just-so story. How to quantify “ambitious”? If the goal were flight, would jumping off cliffs with wings like birds be “ambitious”? The most parsimonious explanation is either our models or methods (or both) are garbage. Something’s missing. The failure rate is insane, and writing it off as ambition or “biology is hard” rather than digging in does us no favors.
- s1artibartfast 3mo ago
  I don't know who you or the article are directing that criticism at. Both models and methods are challenging. Biology is hard. Who isn't digging in exactly? Pharmaceuticals are more than a two trillion dollar market with Millions of scientists and engineers and doctors working diligently to refine the process. There's tens of billions of dollars to gain for any company that comes up with even minor improvements to success rate.
- db48x 3mo ago
  You’ve misunderstood. Nobody here has said that we shouldn’t try to improve the success rate, only that improving the success rate will make people try harder problems which worsens the success rate. If this is true, it just means that any effort you make to improve the success rate really has the effect of improving the quality of our medicines rather than reducing the failure rate. Keep in mind that we’re talking about the success rate of the last step in the process: human trials. For every human trial there were millions of drug candidates that were considered and rejected. Tens of thousands of those candidates were actually synthesized and tested in animal models or in cell cultures. In the 80s these numbers were all lower. Back then only thousands of candidates would be considered, and only hundreds would be synthesized for actual testing. Worse, for every candidate that gets to the human trial stage there were multiple projects that rejected all of their candidates and were discontinued. The numbers here are pretty vague, but past surveys have found that the number of failures at this stage is really high too, maybe as high as 90%. Pharma companies are hardly unaware of this problem. They regularly spend years (even decades) and hundreds of millions of dollars on drug projects that never reach human trials. They spend even more on the ones that reach human trials and then fail. As a result they have spent billions on new methods, new systems, new techniques, etc, all intended to reduce that risk. It appears that all they have managed to do is keep pace with the increasing difficulty of drug development. I don’t necessarily agree that this is inevitable, but it is understandable. > The most parsimonious explanation is either our models or methods (or both) are garbage. I disagree with that. In spite of the difficulties we have managed to get around 50 new drugs approved every year for the last several decades. Sometimes more, sometimes less, of course, but as far as I know there’s been no obvious trend upwards or downwards. That doesn’t seem like garbage to me. > If the goal were flight, would jumping off cliffs with wings like birds be “ambitious”? Not any more, no, but it was quite ambitious back in the 1890s. Back then there was a single scholarly study on the lift generated by wings, and it was completely wrong. The Wright brothers built their own wind tunnel and ran their own tests to get reliable data to base the Flyer’s wings on.
deleted 3mo ago
[deleted]

s1artibartfast 3mo ago

Keytruda revenue is 30+ billion per year. If your new drug performs 1% better than Keytruda, that revenue becomes yours. If your drug perfroms 1% worse, you become a failure in the statistics.

bonsai_spool 3mo ago
That isn’t how a rational person would pursue this - it costs $1B to make a drug start to finish, and there’s no reason to believe your new mechanism will work. If you’re talking about copycat mechanisms, that is fine but we’re still left discussing successes when OP is about failures
- s1artibartfast 3mo ago
  Why isnt it rational? You spend the 1 billion for a ticket to win 30 billion/yr for the next several years. Is it rational to spend 1$ to make $100 10% of the time? A 99% failure rate would be break even.
  - bonsai_spool 3mo ago
    > Why isnt it rational? You can spend that $1B to win a new category or that same money to maybe be non-inferior to Keytruda, but maybe fail. I think copycat design does happen, but I mostly notice it when drugs are being developed simultaneously at different firms. Perhaps it happens more beyond this, I'm unsure. Otherwise, it makes more sense to try to find an indication where you are approved and have no competition.
    - s1artibartfast 3mo ago
      I don't think you are looking at this from the rational economic perspective. I'm not talking about biosimilars or strict copycats. Completely novel indications are a tiny portion of Pharma development. Lucrative and technologically viable untreated indications are few and far between. Meanwhile, you have huge proven markets for treatments that impact millions of people with corresponding Revenue. If you are skeptical, you can simply go look at the development Pipelines for the top 10 pharmaceutical Giants and see how many of their new programs are for indications with existing treatments versus orphan. In recent years, approximately one-third of all novel new drugs approved annually by the FDA have carried a Breakthrough Therapy Designation. This corresponds to drugs that claim a substantial improvement over the standard of care for their target disease.

evandijk70 3mo ago

Lots of reasons. The new drug could be cheaper to manufacture, fewer side effects, a full cure in stead of a functional cure.

bonsai_spool 3mo ago
Cost of manufacture is not a meaningful driver of pricing outside the biological How will your clinical trial of the ostensible full cure work if standard of care is curing people?
- evandijk70 3mo ago
  A full cure would probably have less side-effects, since a functional cure means a life-long dependence on drugs.

inglor_cz 3mo ago

"Why would anyone make a drug if the current prevalent treatment was as good as a functional cure?" I am not sure whether you ask for economic why, or an overall why. The overall why seems easier to explain: a. The new drug may be cheaper. b. The new drug may be safer. (e.g. no risk of anaphylaxis etc.) c. The new drug may not need cold storage (huge problem outside the First World). d. The new drug may have other properties that the original does not have (e.g. being taken once a day instead of four times a day, not requiring people to stay off specific food etc.) e. The side effects (such as vomiting) may be lower. In general, it is always better to have alternatives in medicine.

bonsai_spool 3mo ago
This is very facile thinking - are there any examples of a-e in the real world (namely, a brand new drug program was spun up to exploit a-e) ? I think not, which is why I asked the question.
- inglor_cz 3mo ago
  IIRC there are serious attempts at "vaccination plasters", which would solve the cold storage problems of classical vaccines. Some really bad infections survive in reservoirs far from the closest hospital with reliable electricity. And frankly your comment about "facile thinking" is totally unwelcome. Have you seen someone vomiting their guts out after chemo? That is torture. Oncology is one field where every less punishing treatment would be useful. Some patients have to be taken off otherwise life-saving treatments because they cannot tolerate them. That is true even with well-treatable cancers such as Hodgkins, which 90+ per cent of patients survive.
  - bonsai_spool 3mo ago
    I have seen these people, but we are speaking about drug companies making new drugs. I am not aware of an example of a new chemotherapeutic developed to reduce the side effects of a previous agent - that seems even less reasonable from an ROI perspective since we have good agents to control chemo-associated nausea. (edit) If a new agent happens to cause fewer side effects, that is welcome. But how would you justify the risk of the new agent not working at all? The search for different formulations of an active agent seems a little unrelated (sibling comment to yours) but I concede that I didn't exclude that in my earlier argument. -- My point is that several posters here are giving arguments from first principles ('yes of course we would want to keep trying to make more medications because more options is better than fewer options') but not engaging with the enormous cost such a rationale would entail.