[db48x]

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.

[peyton]

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]

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]

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.