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Clinical failure rates over the decades: yikes

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Re: Clinical failure rates over the decades: yikes

#41

Post by refurb »

As someone who used to work in pharmaceutical R&D, the important thing to remember is the hurdle to get over hasn’t remained constant.

The FDA has gotten significantly more strict in its review than it was in the 1960s.

A good example is hERG inhibition as an off-target effect. It’s a receptor on heart muscles and will result in QT prolongation and potential arrhythmias.

It wasn’t discovered until the 1990s. Now every molecule is screened and many are dumped. The impact can vary but there are tons of drugs on the market now that are hERG inhibitors (many discovered after the fact).

It’s a good example of the increased rigor that the FDA applies to everything they review that past trials never had to face.

Re: Clinical failure rates over the decades: yikes

#42

Post by refurb »

roenxi wrote: post #18

> I’m fond of saying that the most important single statistic about the drug industry is the clinical failure rate, which is (by any reasonable standard) appallingly high. He starts off on the wrong note, there is nothing at all wrong with a high rate of clinical failures. If anything, the reasonable argument standard might be that this rate is too low. It implies researchers are trying things that they expect to hav…

> Failed attempts cost society nearly nothing

The world does not have unlimited resources. Money spent on one project is money that can’t be spent on another.

Re: Clinical failure rates over the decades: yikes

#43

Post by oatmeal1 »

halperter wrote: post #23
roenxi wrote: post #18

> I’m fond of saying that the most important single statistic about the drug industry is the clinical failure rate, which is (by any reasonable standard) appallingly high. He starts off on the wrong note, there is nothing at all wrong with a high rate of clinical failures. If anything, the reasonable argument standard might be that this rate is too low. It implies researchers are trying things that they expect to hav…

Rather notably, companies are profit-driven, not good-for-society driven. If 99% of your attempts which cost millions to do fail, the company either has to raise the prices of the drug insanely high or not work as a company. In addition, most drugs aren't humanity saving or crucial for humans to live. You could solve all forms of cancer tomorrow, which would be a great thing, but you aren't "saving humanity". You add…

Curing all cancer would be bad for the world, because 90% of those cancer kills are old people.

Re: Clinical failure rates over the decades: yikes

#44

Post by mmooss »

refurb wrote: post #41

As someone who used to work in pharmaceutical R&D, the important thing to remember is the hurdle to get over hasn’t remained constant. The FDA has gotten significantly more strict in its review than it was in the 1960s. A good example is hERG inhibition as an off-target effect. It’s a receptor on heart muscles and will result in QT prolongation and potential arrhythmias. It wasn’t discovered until the 1990s. Now ever…

It's interesting that you frame it as the FDA increasing regulation and not that science has increased its foreknowledge of problems.

Re: Clinical failure rates over the decades: yikes

#45

Post by bonsai_spool »

s1artibartfast wrote: post #34
arjie wrote: post #31

Can’t agree with the premise. It seems that through changing regulatory regimes and technology a 1 in 10 chance is the economic optimum for this. Interesting stability, certainly, but I’d expect that as technology improves success rate, funding increases until the marginal project is unprofitable. The better we get at doing things, the more ambitious we get. As an example, we can keep babies alive much earlier in ges…

I 100% agree. the criteria for sucess is something that is missed by simplyifying things to a number. Those failures can include drugs that would be considerer miraculous 10 or 20 years ago. You might have a drug that functionally cures HIV, but failed to outperform the standard of care in a RCT. You have drugs like Lorbrena for non-small cell lung cancer where the median life extension is unknown because >50% of pat…

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?

Re: Clinical failure rates over the decades: yikes

#46

Post by db48x »

bonsai_spool wrote: post #45
s1artibartfast wrote: post #34

Earlier quoted context omitted.

I 100% agree. the criteria for sucess is something that is missed by simplyifying things to a number. Those failures can include drugs that would be considerer miraculous 10 or 20 years ago. You might have a drug that functionally cures HIV, but failed to outperform the standard of care in a RCT. You have drugs like Lorbrena for non-small cell lung cancer where the median life extension is unknown because >50% of pat…

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?

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.

Re: Clinical failure rates over the decades: yikes

#47

Post by peyton »

db48x wrote: post #46
bonsai_spool wrote: post #45

Earlier quoted context omitted.

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?

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.

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.

Re: Clinical failure rates over the decades: yikes

#48

Post by s1artibartfast »

TheOtherHobbes wrote: post #7
levocardia wrote: post #4

Earlier quoted context omitted.

Indeed, I suspect the failure rate of, say, new jet engine designs is rather high as well -- those failures just never get reported in a federal repository, unlike RCTs, since they never make it out of the simulator or the prototyping lab. And we have, comparatively, much better computational models of how airplanes fly than how cancer cells mutate. FWIW this clinical stat is far better than Edison's supposed lightbu…

Jet engine design is iterative, and the basic principles are well-understood. Drug design seems a lot more binary. You can find a new pathway, but drugs themselves are fairly simply molecules, and you can't iteratively 'fix bugs' the way you can in an engine or a piece of software. The engine is a given, it's almost astronomically complicated, you know a lot less about how it works than you'd like to, and you're tryi…

This is a pretty outdated view, particularly with respect to biologics, which are some of the most complex structures humans fabricate. Many are in fact quite similar to iterative prototypes of jet engines.

You might have something like Anti–vascular endothelial growth factor therapy, where you have a binding target structure, and iterate the uses and molecular structure around it, or combine it with other structures and binding sites.

You might go from mab to fab, or to bispecific mab using CrossMab IgG architecture, or bispecific fab using dutafab fragment architechture. This analogizes to mixing and matching different jet engine technologies into different platofrms.

VEGF targeting biologics have netted >150 billion dollars to date, and this will only grow faster in the future.

iterative GLP-1 technologies will be much the same, where people are literally iteratively fixing bugs.

The development pipeline for both is littred with failed iterations.

Re: Clinical failure rates over the decades: yikes

#49

Post by mlyle »

calf wrote: post #39
EA-3167 wrote: post #9

Earlier quoted context omitted.

How? He’s saying that he can’t think of any good ones, and in my experience that’s true of most informed people. This is one of those hard problems that needs solutions, and so far the present system is the best anyone has managed.

I don't care what he's "saying that" which is just your biased interpretation. His essay does not warrant the final concluding sentence which would require a different essay thesis. It's just basic high school reading and writing skills.

Again, anyone who cracks a decent success rate can basically print money. Unfortunately, despite lots of efforts in this area, we have not been able to get the clinical success rate up.

It's pretty low effort to jeer from the outside and say "do better" for an industry that's been trying so many approaches to do so, without any ideas yourself.

The techniques have gotten a lot more sophisticated, but unfortunately a lot of the low hanging, "easy" fruit have been used up. Biology is hard.

Re: Clinical failure rates over the decades: yikes

#50

Post by s1artibartfast »

bonsai_spool wrote: post #45
s1artibartfast wrote: post #34

Earlier quoted context omitted.

I 100% agree. the criteria for sucess is something that is missed by simplyifying things to a number. Those failures can include drugs that would be considerer miraculous 10 or 20 years ago. You might have a drug that functionally cures HIV, but failed to outperform the standard of care in a RCT. You have drugs like Lorbrena for non-small cell lung cancer where the median life extension is unknown because >50% of pat…

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?

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.
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