Comment by bonsai_spool

A full cure would probably have less side-effects, since a functional cure means a life-long dependence on drugs.

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.

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.

You could compare ibuprofen and naproxen. One lasts 4-ish hours while the other, having different functionality, lasts 12-ish hours.

I dont know why you are being rude about a topic you know nothing about. As some who actually does this for a career, they are largely correct. Dose frequency and side effects especially are major reasons. I would add route of administration and patient convenience as well.

Anti-vegf treatments for blindness are a good example if you want to research. They all have basicly the same effect in terms of letters preserved on an eye chart if dosed as perscribled.

It's a 15 billion dollar per year Market that resolves on the basis of the longest dose interval and side effects.

You can look at the bevicizumab, to ranibizumab, to aflibercept, to brolucizumab, to faricimab drug programs. There are also dozens of failed programs in this area and perpetually new drugs and Gene Therapies looking to break into the market.

Perhaps an even more salient example would be pill based GLPs looking exploit the listed factors

What an ignorant comment. Are you not familiar with Mavyret, Vosevi, or Xatmep?

Look at the GLP-1s. Lilly spent tens hundreds of millions developing an oral version that was otherwise the same as the injectable’s.

And the notorious inhaled insulin that Pfizer launch (and horribly failed).

There are many ways to differentiate drugs, not just efficacy.

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.

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.