8 ms·

Clinical failure rates over the decades: yikes

145 points by EA-3167 3mo ago

perpetuallunch 3mo ago
This is completely unsurprising, and this: But let’s think about that 91% failure rate for a moment. When I bring this up in presentations, I invite the audience to consider what the auto industry would look like of 91% of new car designs proved unable to roll out of the factory, or if 91% of new airliner models were unable to leave the ground Is an utterly irrelevant comparison. For physical thing we have engineering, and the practical application of the trades and craft, trial and error. For modern medicine, we're only just starting to come out of the wild west era. Or perhaps slightly further along than that.
- levocardia 3mo ago
  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 lightbulb-idea failure rate!
  - TheOtherHobbes 3mo ago
    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 trying to change how it works while it's running without breaking anything, using tiny rigid parts that have to snap into place correctly and can't be bent to fit. High failure rates aren't surprising.
    - s1artibartfast 3mo ago
      This is a pretty outdated view, particularly with respect to biologics, which are some of the most complex structures humans fabricate.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.
- estearum 3mo ago
  > For modern medicine, we're only just starting to come out of the wild west era. Or perhaps slightly further along than that. Why do you say that? What's the evidence? We continue to have virtually no clue how to make drugs, per TFA.
  - perpetuallunch 3mo ago
    Targeted gene therapy, cancer survival rates, trauma care, the advancements in hip and knee replacement, all sorts of surgery, HIV is now a non-issue with the right care. The list goes on. Drug development is a hard problem because the solution space is poorly constrained: biochemistry is complex and messy, expecting one chemical substance to have narrow positive effects is probably hopeless.
    - estearum 3mo ago
      ...? So the claim is that we're out of the wild west because there's a set of things we've made advancements on, despite drug development getting harder and harder?
      - preg_match 3mo ago
        Consider drug development becomes harder because we've gotten so good at it. Basically all the low-hanging fruit is long gone. We have very reliable and effective drugs and vaccines for illnesses which DESTROYED humanity before. The only reason people are even dying from cancer at such high rates is because we solved other easier illnesses, and people live way longer as a result. People 100 years ago weren't dying to cancer like they are now, because they were already dead from other more common, simpler, diseases. Something like cancer is extraordinarily complex. It's nothing like a bacteria or a virus. I mean, think about it, we have to devise methods of targeting cancer cells without injuring human cells around them - when the bodies own immune system cannot differentiate them. And we have devised those methods! Chemotherapy, immunotherapy, radiation therapy. It's truly incredible.
        3mo ago
- bsder 3mo ago
  > Is an utterly irrelevant comparison. For physical thing we have engineering, and the practical application of the trades and craft, trial and error. > > For modern medicine, we're only just starting to come out of the wild west era. Or perhaps slightly further along than that. I don't think its irrelevant, but a better comparison would be to what vacuum tube development looked like before we understood electrons. There were some very whacky designs and most of them didn't work for crap. And, yeah, I would argue that PCR shifted us from the alchemy phase of biology to the science phase and now mRNA has shifted us from the science phase of biology to t he engineering phase of biology. We're just getting started.
- mianos 3mo ago
  Also, highly related, in the previous paragraph, they say: "We know a lot more about the biology of disease - although God knows, not nearly enough". Anyone smarter than a 10 year old would not we actually know almost everything about car design. How it works is not at all hidden. We have iterated on pretty much the same thing for 100 years. The current state is about efficiency, materials and manufacturing. When you have deep knowledge and experience in a field you will get near 100%.
- bawolff 3mo ago
  If someone said, 91% of software projects fail, i would beieve them.
- amelius 3mo ago
  > For physical thing we have engineering, and the practical application of the trades and craft, trial and error. > For modern medicine, we're only just starting to come out of the wild west era. Or perhaps slightly further along than that. You could say the same about deep learning. Yet we see improvements every day.
- preg_match 3mo ago
  And, moreover, the human body is much, much more complex than any plane or car. We know how cars work and how planes work. For many parts of the human body, we don't know exactly how they work. We have multiple hypothesis, maybe, but we can't say "oh yes this is how serotonin works in the brain". We might know the small scale interactions, but why do SSRIs work in terms of the entire brain? We don't know. Why and how does anesthesia work? We also don't know.
levocardia 3mo ago
I'm actually surprised it isn't going up over time. That is naively what you would expect as the low-hanging fruit is plucked. So the fact that it's been stable is probably a sign that scientific advances are roughly keeping pace with the (presumably) increasing challenge of finding ever more targets for drugs.
- CamperBob2 3mo ago
  He points out that it basically has gone up, since the 80s and 90s brought some new therapeutic targets and approaches that by now have been mined out.
- bwhiting2356 3mo ago
  I suspect there's a ceiling on failure rates people are willing to operate under. A diversified investor might still be willing to take high risk/reward bets. But workers can go their whole career producing nothing of value. It becomes hard to tell the difference between smart, hard working people who were unlucky and lazy grifters. I've done 2 series-A startups and I don't think I can do another one.
- a_bonobo 3mo ago
  I actually do this for a living within pharma now! There's a TON of work that goes into drug discovery before we even call it a program. The odds of success are low, so we put in months of work evaluating a candidate before even have a hunch of a program. Yes, the science advances, previously high-hanging fruits become low-hanging become high-hanging again [1], but the tooling also advances: we now have databases like OpenTargets which let us more easily evaluate potential drug targets. Failure is so much more than that, though: a program can fail after you've shown efficacy in animals, sometimes it just doesn't happen in the human subjects. Or you fail to find the right measurement (endpoint). A million ways to die. [1] Gene editing is an example: impossible, then very possible, but now the blocker is public perception which in turn blocks investment.
  - ip26 3mo ago
    Is public perception the greater problem, or delivery? My outsider read has been relatively few diseases can be targeted right now due to payload delivery obstacles
AbsurdCensor 3mo ago
As someone who works in research, this isn’t surprising at all. It’s hard to find something that treats (well most often reduces symptoms) of a particular disease. It’s even more difficult to find something that is also safe at the dose level it takes to treat said disease. Are there faster ways to do this? Probably not. AI is only going to help out so much, just like automated drug screening only helped so much since its introduction in the 90s.
calf 3mo ago
Why does he conclude there is no alternative? He already argued this would be strange in other disciplines. So reform it.
- mlyle 3mo ago
  If you can think of a way that you can have a much higher chance than 9% of success in getting a useful treatment to market, you can make a boatload of money. Go ahead, reform it.
  - calf 3mo ago
    Not knowing of a way is inequivalent to inexistence of any way. This is basic and apparently some bloggers are bad writers and or political conservatives of the type "there is no alternative".
    - estearum 3mo ago
      The alternative is "have a complete mechanistic understanding of biology." People are definitely working on it, but we are nowhere close to as complete an understanding as we need. The evidence for precisely this claim is in the failure rate of clinical trials, into which we encode our best-known understanding of biology and we still end up being wrong 90% of the time. And that's not including all the pre-clinical candidates, which drive our wrongness rate (i.e. knowledge gap) to 99.99999%+
- EA-3167 3mo ago
  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.
  - calf 3mo ago
    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.
debo_ 3mo ago
There's an alternative that is slowly emerging. Many clinical trials "fail" but the drug candidate in question works really well for identifiable subsets of the participants. Right now pharma companies won't bother pursuing those drugs because they can't market it broadly. But it's still possible these drugs could help people in the future.
- estearum 3mo ago
  Not really an alternative if you can't predict who those candidates are prior to spending a hundred million dollars putting the drug into a broader group of people and then retroactively saying "oh wait now we can 'identify' who it works in." If they could do that today, they would. Trial criteria are already incredibly narrow specifically to try to encode as much of this knowledge as the company has prior to starting the trial. But it empirically turns out they don't have nearly enough to matter. It's really not a problem that pre-filtering to that responders group produces too small a market. There are plenty of drug programs going after way-too-small markets because of all these wacky perverse incentives created by insurers and regulators to incentivize the creation of billion-dollar++ drugs for diseases virtually no one has.
jcims 3mo ago
Roughly equivalent to the percentage of startups that fail. Lower numbers don’t mean we’re doing better, it means we’re trying less.
- m463 3mo ago
  lower numbers might be play to not lose, instead of play to win. On the other hand, do no harm. ugh, I don't know
- BobbyTables2 3mo ago
  I’m not entirely sure other startups necessarily want to succeed… Their goal often seems not to be toward a successful, sustainable product. They just market their vision in the hopes of being acquired. A few fewer failures might not be entirely a bad thing.
  - throwaway27448 3mo ago
    Isn't this the entire point of vc culture? Builders are rubes; investors are the smart kids who can cash out before their investment collapses. The missing ingredient of course is the people. We cannot let this country pretend it's functional when it invests so poorly. Any sane version of the us will expect years if nit decades of economic pain before these investments pay off
roenxi 3mo ago
> 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 have a 10% chance of working out. That means we're missing out on all the cures and techniques that have a 1% chance of working out but but nonetheless do work. Failed attempts cost society nearly nothing and successes will have compounding benifits for, y'know, lets optimistically say the human race survives for centuries. 1% or 0.1% success rates sound completely reasonable with that sort of lopsided risk profile. There isn't much of a reason not to try anything and everything that has the faintest chance of helping and see what happens.
- DivingForGold 3mo ago
  Except that governing bodies approve many of these drugs which, further down the line, consumers may experience high failure rates or even toxicity, which in other industries such results would be considered outright fraud subject to legal action. if sold to consumers.
- halperter 3mo ago
  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 less than a decade or so, maximum, to the average human lifespan. This isn't critical to humanity's existence, so this "try or die" mentality doesn't work. If this try or die mentality does work, why don't we try every possible amino acid chain in every configuration possible? It's an infinitesimally small chance but try or die "outweighs". This is evidently absurd.
  - roenxi 3mo ago
    Lowe mentions costs 0 times though, he isn't making an economic argument. If you want to make an economic argument then 90% is probably the consensus on what is optimal given that is what people are doing. > If this try or die mentality does work, why don't we try every possible amino acid chain in every configuration possible? You tell me. If someone wants to start working through the amino acids one by one I'm not going to say they should be stopped; sincerest good luck to them. I'm just not going to be the one funding it. > You could solve all forms of cancer tomorrow, which would be a great thing, but you aren't "saving humanity". This is a straw man. "Saving humanity", whatever that means, is outside the scope of medicine and I never argued for it. Nobody did. It isn't relevant.
tchalla 3mo ago
I’ve been hearing for 10 years now on how “AI” will change this clinical rate. It’s now like the “This is the year of Linux” prediction meme. And like Derek has mentioned multiple times you can’t statiscialise biology. I don’t think many people get it so we have tech bros like us throw AI at data.
- Fomite 3mo ago
  I've been hearing some form of it since I was an undergrad. I just submitted by packet for full professor. There have been some spectacular strides, but we've been through multiple rounds of "Stand aside, the computers will take it from here."
- asdff 3mo ago
  People saying this stuff aren't in the game. ML has been used in clinical research for basically as long as various ML methods have been around. Basically a century now in other words. AI leaders are trying to get money from people who don't understand the methodology such as investors or trump administration officials. Imagine trying to convince people who actually work day in day out with classic ml and deep learning to use your llm goobly goop bot.
  - tchalla 3mo ago
    Yeah ML is used in clinical research but the narrative right now is that "AI" will take a target, find a molecule and we will magically have a safe drug in 3 years instead of 12 years. At best, it misunderstands biology and chemistry. At worst, it's one of those tech bro reductive statements. Even today, I am on a newsletter that has said AI drug will pass clinical trial in 2022 ... 23 .. 24 .. 25. Even the candidates that they talk about are mostly just repurposing. Don't get me wrong, ML has a solid place in clinical research but not like this.
Fomite 3mo ago
Doing hard things is hard.
arjie 3mo ago
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 gestation, so we try harder if they’re earlier than we would before. We should expect a homeostatic equilibrium between our skill and our ambition.
- s1artibartfast 3mo ago
  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 patients are alive 7 years out. Or Keytruda where 50% of advanced melenoma patients appear functionally cured 10 years post treatment.
  - bonsai_spool 3mo ago
    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.
Plasmoid 3mo ago
The author, Derek Lowe, also writes the hilarious Things I won't work with series (https://www.science.org/content/blog-post/things-i-won-t-work-dioxygen-difluoride https://www.science.org/content/blog-post/things-i-won-t-wor...)
refurb 3mo ago
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.
- mmooss 3mo ago
  It's interesting that you frame it as the FDA increasing regulation and not that science has increased its foreknowledge of problems.
  - refurb 3mo ago
    It’s a similar problem you see with all safety related decisions - as the large risks are eliminated you become more concerned about the smaller risks. Plenty of successful drugs from the 50’s had hERG activity, yet the impact on safety was marginal. Today plenty of programs are killed over it. Increase safety scrutiny does increase safety, but at a cost.
    - mmooss 3mo ago
      > Plenty of successful drugs from the 50’s had hERG activity, yet the impact on safety was marginal. Is there some evidence of these two claims? Obviously many experts think otherwise.
      - refurb 3mo ago
        Lots of examples of older drugs currently in use that are potent hERG inhibitors: haloperidol (antipsychotic), ketoconazole (antifungal), erythromycin (antibiotic), domperidone (anti-emetic), hydroxychloroquine (anti-malarial). All of these are rather potent hERG inhibitors, yet were approved and widely used before that activity was discovered. Pulling them off the market would have been quite disruptive considering some of them are the only effective treatment for rather serious diseases. Of course it's a matter of opinion, but I would argue some of these workhorse medications would have had their program killed by the manufacturer (fear the FDA won't approve) or the FDA itself (risk of fatal arrhythmias) if they were developed today. Yet the risk is managed by flagging the contraindication when combined with other drugs (since the inhibition is often additive).
_3u10 3mo ago
Umm restaurants ARE like that, why do you think there’s so many burger and pizza joints?
- deleted 3mo ago
  [deleted]
pinkmuffinere 3mo ago
> But let’s think about that 91% failure rate for a moment. When I bring this up in presentations, I invite the audience to consider what the auto industry would look like of 91% of new car designs proved unable to roll out of the factory, or if 91% of new airliner models were unable to leave the ground - and if you only found that out after spending all the R&D money to build them at full size and trying to fly them. No cutting-edge restaurant could survive if 91% of its innovative dishes proved inedible or outright poisonous. What other industries operate under these bizarre conditions? This is bizarre, bordering on stupid. Frist of all, there likely is ~90% failure rate of prototypes; I feel that roughly matches my experience in engineering. Of course the design that makes it through the process, testing, refinement, and into mass production is not going to have a 90% failure rate, but that's a _finished product_, whereas clinical tests are just that -- tests. Finished cars are more analogous to individual pills coming out of the factory. And I'm not even sure the analogy would be very meaningful anyways, because we have different requirements for things of different impact and importance. A 10% manufacturing defect rate is fine in forks, but not for fire extinguishers.
- fabian2k 3mo ago
  A large part of that failure rate is in phase 3. Your comparison with prototypes would be more like drug development before even phase 1. Phase 3 is enormously expensive, much more than the earlier parts. And what's even worse, you don't get to learn all that much from failures in drug development in many cases. You can't just fix the problem and try again, you essentially have to try a completely new molecule.
  - pinkmuffinere 3mo ago
    That's fair, phase 3 testing isn't an early prototype, it's a prototype with many years of effort behind it. But I still think it is _more_ like a prototype than it is like a product coming off an assembly line. Perhaps phase 3 is like the latest prototype from boom (the company trying to bring back super-sonic jets). Those prototypes represent 100s of engineering-years put together, and are not much like the prototypes you'd encounter in consumer product development. I still think 90% failure rate is believable for that. How many significant design iterations has Boom gone through so far? I don't really know, but I could believe it's been 10 significant iterations.
asdff 3mo ago
You want high failure rates. If failure rates were low, that tells you that you are probably being far too conservative in funding new clinical trials.
contubernio 3mo ago
Without doing any serious thought, it is concerning that the statistic doesn't vary more temporally. It seems too consistent, and raises the suspicion that it reflects regulatory agenda more than anything intrinsic
- akk0 3mo ago
  Going from an 80% to a 90% failure rate means the success rate halved; that's a pretty big change in my book.
L-four 3mo ago
If failure rates went down wouldn't that increase the number of clinical trials until the failure rates go back up.
qsera 3mo ago
>So when we do get something to work and something that people are willing to pay money for, we try to squeeze every dollar out of it because we never know when the next one will come along. Would make a small correction. It does not have to be people. It can be also be "doctors" or "governments". It is easier to convince or coerce/fool a lesser number of humans (doctors) or a single government regulatory body than to fool/convince every one who use the product, because the people can directly evaluate the product. And when a single doctor is coerced, then the product is forced on hundreds of their patients. When a government is coerced, then the product is forced on tens of millions of people..
- akk0 3mo ago
  Doctors are people
  - qsera 3mo ago
    But they are not the one paying for the drugs they prescribe...
mbnielsen 3mo ago
Many comments so far seem to try to handwave away the 90 % failure as somehow "optimal" in the system, which seems absurd to me. It is clearly not advantageous for individual companies to keep a drug candidate alive long enough for it to fail in stage III or IV. One obvious question is why they don't and it is very, very tempting to speculate that it's because the problems are getting harder, we are targeting novel mechanisms etc. Again, I think this misses a simpler explanation: As with many cases where companies make seemingly bad decisions, I think a lot of the explanation lies in system dynamics. Think about the incentive structure inside large pharma companies - it is generally not a career advancement move for a project manager to kill the drug candidate they oversee. It is career advancing to get it approved for the next stage. What could possibly go wrong in this world?
- rwmj 3mo ago
  Sure, but Pharma A is full of career managers who never kill drugs under development and Upstart B relentlessly culls drugs that don't work early on. Upstart B's failure rate at the final stages is under 50% so they develop 5 times as many drugs, beating the existing company, and indeed all other drug companies. Since this isn't happening, it seems this might not be the explanation.
  - ozim 3mo ago
    For me it seems this simplification falls flat right away when you take into account budget constraints. It is not software development where you can start a project every month see how it goes and drop it or pivot. I guess they use a lot of computer aided models before they even start serious parts but I believe this discussion is not about failure rates on that stage because then it would be 99%
- logicchains 3mo ago
  The human body is an extremely complex system. Simulating it completely accuracy would require a computer many orders of magnitude more powerful than anything currently existing, so the only way to know if a treatment doesn't produce any unexpected side effect is years of empirical testing, because such things can take years to manifest. Fundamentally the problem space contains inescapable complexity; it's not the fault of pharma firms.
braiamp 3mo ago
I had to look what "clinical failure rate" means and I think I got the answer in this paper [1] and... I'm not going to say that it is worrisome. Unlike other industries, we can't accurately model in the pre-prototype phase how something will behave in living beings. And to use the author examples, cars and airliners are big and way simpler to model than the complex pathways that you find in biology. We are chipping away at that problem but it's not like we have it mostly solved as other engineering areas of knowledge. I would argue that due that phase I successes isn't the benchmark, but phase II success should be the actual measure. I'm sure that if someone charts the accumulative success rate for each phase of clinical trials, you will see that phase I is the most brutal one. 1: https://www.nature.com/articles/nrd.2016.136 https://www.nature.com/articles/nrd.2016.136
- officialchicken 3mo ago
  > I had to look what "clinical failure rate" means That should have been the end if the comment; the follow-up by demonstrating such expertise just has me laughing.
  - deleted 3mo ago
    [deleted]
timedude 3mo ago
This is no surprise. Read "Confessions of a Medical Heretic" https://www.amazon.com/Confessions-Medical-Heretic-Robert-Mendelsohn/dp/0809241315/ https://www.amazon.com/Confessions-Medical-Heretic-Robert-Me...
xvxvx 3mo ago
Animal rights campaigners like PETA have been saying this for decades: https://www.peta.org/issues/animals-used-for-experimentation/animals-used-experimentation-factsheets/animal-experiments-overview/ https://www.peta.org/issues/animals-used-for-experimentation... 110M+ animals suffering and dying for nothing each year. And people ask why I choose cruelty-free.
doadfda 3mo ago
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pmarreck 3mo ago
Finally, something that makes the current state of software development look GOOD!
tsoukase 3mo ago
Drug discovery and development is hard, unique and non comparable in the engineering world. It has it's own properties, like "the pipeline", I-... phases and a mere 20-year long patent duration (counting from molecule discovery). Imagine if after 20 years of it's inception on the paper the car's price falls 5-fold and you have to develop a new machine. The failure rate does not take into account the millions of molecules that are tested by various methods of protein folding or binding properties. The 90% remains stable with time because on one side an end product is more difficult to produce, on the other the technology of molecule discovery has improved in the same amount.
bibouthegreat 3mo ago
People get confused about all the types of clinical trials. The worst part happened in 1997 [1] Before this time, you could p-hack your studies. You could get a molecule and just look at some random effect that happens in any case because of sampling issues. Since 1997, you must register the full protocol to the FDA before the study. Since then, almost no study with a full protocol brought a really new medicine. [1] https://en.wikipedia.org/wiki/Food_and_Drug_Administration_Modernization_Act_of_1997 https://en.wikipedia.org/wiki/Food_and_Drug_Administration_M...
tim333 3mo ago
>It’s a nerve-wracking way to live, but there’s no alternative in sight. There's always AI simulation on the way. Deepmind's Isomorphic labs is working on it https://www.isomorphiclabs.com/articles/the-isomorphic-labs-drug-design-engine-unlocks-a-new-frontier https://www.isomorphiclabs.com/articles/the-isomorphic-labs-... And an AI designed drug for idiopathic pulmonary fibrosis from Insilico Medicine is going to clinical trials https://www.artificialintelligence-news.com/news/insilico-medicine-advances-ai-drug-for-ipf-to-phase-iii-trials/ https://www.artificialintelligence-news.com/news/insilico-me...
alan-crowe 3mo ago
People with serious illnesses long to get on to a clinical trial, hoping to get the latest and best treatment, even before it is approved. But it is not really like that. Only one phase III drug in ten really helps. And what of the other nine? Derek Lowe doesn't go into the downside, so I'm left to guess that eight out of ten do neither good nor harm and one in ten get their trial stopped in a panic when they turn out to be harmful. By all means volunteer for a clinical trial as an altruistic act, hoping to advance science and confer a benefit on those who come after. With such a high failure rate, the expected benefit is likely net zero.
maerF0x0 3mo ago
In addition to many others commenting that a great defense is to reject a lot of things. But also it strikes me, perhaps we're also approaching the limits of "drugs" as in compounds delivered by topical, oral ingestion, injectable etc? Perhaps the human creature needs upgrades that go beyond "just add chemicals systemically"? I'm thinking of things like targetted delivery by nanobots, gene editing, replacing body parts with engineered/mechanical versions... For example maybe we can obviate statins for those who have genetically high cholesterol by editing their genes, or maybe just replace the failing biological pump (heart) with a mechanical one? (Cue all the folks with the "One does not simply" memes :) )

145 points by EA-3167 3mo ago

This is completely unsurprising, and this: But let’s think about that 91% failure rate for a moment. When I bring this up in presentations, I invite the audience to consider what the auto industry would look like of 91% of new car designs proved unable to roll out of the factory, or if 91% of new airliner models were unable to leave the ground Is an utterly irrelevant comparison. For physical thing we have engineering, and the practical application of the trades and craft, trial and error. For modern medicine, we're only just starting to come out of the wild west era. Or perhaps slightly further along than that.

levocardia 3mo ago
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 lightbulb-idea failure rate!
- TheOtherHobbes 3mo ago
  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 trying to change how it works while it's running without breaking anything, using tiny rigid parts that have to snap into place correctly and can't be bent to fit. High failure rates aren't surprising.
  - s1artibartfast 3mo ago
    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.
estearum 3mo ago
> For modern medicine, we're only just starting to come out of the wild west era. Or perhaps slightly further along than that. Why do you say that? What's the evidence? We continue to have virtually no clue how to make drugs, per TFA.
- perpetuallunch 3mo ago
  Targeted gene therapy, cancer survival rates, trauma care, the advancements in hip and knee replacement, all sorts of surgery, HIV is now a non-issue with the right care. The list goes on. Drug development is a hard problem because the solution space is poorly constrained: biochemistry is complex and messy, expecting one chemical substance to have narrow positive effects is probably hopeless.
  - estearum 3mo ago
    ...? So the claim is that we're out of the wild west because there's a set of things we've made advancements on, despite drug development getting harder and harder?
    - preg_match 3mo ago
      Consider drug development becomes harder because we've gotten so good at it. Basically all the low-hanging fruit is long gone. We have very reliable and effective drugs and vaccines for illnesses which DESTROYED humanity before. The only reason people are even dying from cancer at such high rates is because we solved other easier illnesses, and people live way longer as a result. People 100 years ago weren't dying to cancer like they are now, because they were already dead from other more common, simpler, diseases. Something like cancer is extraordinarily complex. It's nothing like a bacteria or a virus. I mean, think about it, we have to devise methods of targeting cancer cells without injuring human cells around them - when the bodies own immune system cannot differentiate them. And we have devised those methods! Chemotherapy, immunotherapy, radiation therapy. It's truly incredible.
      - 3mo ago
bsder 3mo ago
> Is an utterly irrelevant comparison. For physical thing we have engineering, and the practical application of the trades and craft, trial and error. > > For modern medicine, we're only just starting to come out of the wild west era. Or perhaps slightly further along than that. I don't think its irrelevant, but a better comparison would be to what vacuum tube development looked like before we understood electrons. There were some very whacky designs and most of them didn't work for crap. And, yeah, I would argue that PCR shifted us from the alchemy phase of biology to the science phase and now mRNA has shifted us from the science phase of biology to t he engineering phase of biology. We're just getting started.
mianos 3mo ago
Also, highly related, in the previous paragraph, they say: "We know a lot more about the biology of disease - although God knows, not nearly enough". Anyone smarter than a 10 year old would not we actually know almost everything about car design. How it works is not at all hidden. We have iterated on pretty much the same thing for 100 years. The current state is about efficiency, materials and manufacturing. When you have deep knowledge and experience in a field you will get near 100%.
bawolff 3mo ago
If someone said, 91% of software projects fail, i would beieve them.
amelius 3mo ago
> For physical thing we have engineering, and the practical application of the trades and craft, trial and error. > For modern medicine, we're only just starting to come out of the wild west era. Or perhaps slightly further along than that. You could say the same about deep learning. Yet we see improvements every day.
preg_match 3mo ago
And, moreover, the human body is much, much more complex than any plane or car. We know how cars work and how planes work. For many parts of the human body, we don't know exactly how they work. We have multiple hypothesis, maybe, but we can't say "oh yes this is how serotonin works in the brain". We might know the small scale interactions, but why do SSRIs work in terms of the entire brain? We don't know. Why and how does anesthesia work? We also don't know.

levocardia 3mo ago

I'm actually surprised it isn't going up over time. That is naively what you would expect as the low-hanging fruit is plucked. So the fact that it's been stable is probably a sign that scientific advances are roughly keeping pace with the (presumably) increasing challenge of finding ever more targets for drugs.

CamperBob2 3mo ago
He points out that it basically has gone up, since the 80s and 90s brought some new therapeutic targets and approaches that by now have been mined out.
bwhiting2356 3mo ago
I suspect there's a ceiling on failure rates people are willing to operate under. A diversified investor might still be willing to take high risk/reward bets. But workers can go their whole career producing nothing of value. It becomes hard to tell the difference between smart, hard working people who were unlucky and lazy grifters. I've done 2 series-A startups and I don't think I can do another one.
a_bonobo 3mo ago
I actually do this for a living within pharma now! There's a TON of work that goes into drug discovery before we even call it a program. The odds of success are low, so we put in months of work evaluating a candidate before even have a hunch of a program. Yes, the science advances, previously high-hanging fruits become low-hanging become high-hanging again [1], but the tooling also advances: we now have databases like OpenTargets which let us more easily evaluate potential drug targets. Failure is so much more than that, though: a program can fail after you've shown efficacy in animals, sometimes it just doesn't happen in the human subjects. Or you fail to find the right measurement (endpoint). A million ways to die. [1] Gene editing is an example: impossible, then very possible, but now the blocker is public perception which in turn blocks investment.
- ip26 3mo ago
  Is public perception the greater problem, or delivery? My outsider read has been relatively few diseases can be targeted right now due to payload delivery obstacles

AbsurdCensor 3mo ago

As someone who works in research, this isn’t surprising at all. It’s hard to find something that treats (well most often reduces symptoms) of a particular disease. It’s even more difficult to find something that is also safe at the dose level it takes to treat said disease. Are there faster ways to do this? Probably not. AI is only going to help out so much, just like automated drug screening only helped so much since its introduction in the 90s.

calf 3mo ago

Why does he conclude there is no alternative? He already argued this would be strange in other disciplines. So reform it.

mlyle 3mo ago
If you can think of a way that you can have a much higher chance than 9% of success in getting a useful treatment to market, you can make a boatload of money. Go ahead, reform it.
- calf 3mo ago
  Not knowing of a way is inequivalent to inexistence of any way. This is basic and apparently some bloggers are bad writers and or political conservatives of the type "there is no alternative".
  - estearum 3mo ago
    The alternative is "have a complete mechanistic understanding of biology." People are definitely working on it, but we are nowhere close to as complete an understanding as we need. The evidence for precisely this claim is in the failure rate of clinical trials, into which we encode our best-known understanding of biology and we still end up being wrong 90% of the time. And that's not including all the pre-clinical candidates, which drive our wrongness rate (i.e. knowledge gap) to 99.99999%+
EA-3167 3mo ago
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.
- calf 3mo ago
  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.

debo_ 3mo ago

There's an alternative that is slowly emerging. Many clinical trials "fail" but the drug candidate in question works really well for identifiable subsets of the participants. Right now pharma companies won't bother pursuing those drugs because they can't market it broadly. But it's still possible these drugs could help people in the future.

estearum 3mo ago
Not really an alternative if you can't predict who those candidates are prior to spending a hundred million dollars putting the drug into a broader group of people and then retroactively saying "oh wait now we can 'identify' who it works in." If they could do that today, they would. Trial criteria are already incredibly narrow specifically to try to encode as much of this knowledge as the company has prior to starting the trial. But it empirically turns out they don't have nearly enough to matter. It's really not a problem that pre-filtering to that responders group produces too small a market. There are plenty of drug programs going after way-too-small markets because of all these wacky perverse incentives created by insurers and regulators to incentivize the creation of billion-dollar++ drugs for diseases virtually no one has.

jcims 3mo ago

Roughly equivalent to the percentage of startups that fail. Lower numbers don’t mean we’re doing better, it means we’re trying less.

m463 3mo ago
lower numbers might be play to not lose, instead of play to win. On the other hand, do no harm. ugh, I don't know
BobbyTables2 3mo ago
I’m not entirely sure other startups necessarily want to succeed… Their goal often seems not to be toward a successful, sustainable product. They just market their vision in the hopes of being acquired. A few fewer failures might not be entirely a bad thing.
- throwaway27448 3mo ago
  Isn't this the entire point of vc culture? Builders are rubes; investors are the smart kids who can cash out before their investment collapses. The missing ingredient of course is the people. We cannot let this country pretend it's functional when it invests so poorly. Any sane version of the us will expect years if nit decades of economic pain before these investments pay off

roenxi 3mo ago

> 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 have a 10% chance of working out. That means we're missing out on all the cures and techniques that have a 1% chance of working out but but nonetheless do work. Failed attempts cost society nearly nothing and successes will have compounding benifits for, y'know, lets optimistically say the human race survives for centuries. 1% or 0.1% success rates sound completely reasonable with that sort of lopsided risk profile. There isn't much of a reason not to try anything and everything that has the faintest chance of helping and see what happens.

DivingForGold 3mo ago
Except that governing bodies approve many of these drugs which, further down the line, consumers may experience high failure rates or even toxicity, which in other industries such results would be considered outright fraud subject to legal action. if sold to consumers.
halperter 3mo ago
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 less than a decade or so, maximum, to the average human lifespan. This isn't critical to humanity's existence, so this "try or die" mentality doesn't work. If this try or die mentality does work, why don't we try every possible amino acid chain in every configuration possible? It's an infinitesimally small chance but try or die "outweighs". This is evidently absurd.
- roenxi 3mo ago
  Lowe mentions costs 0 times though, he isn't making an economic argument. If you want to make an economic argument then 90% is probably the consensus on what is optimal given that is what people are doing. > If this try or die mentality does work, why don't we try every possible amino acid chain in every configuration possible? You tell me. If someone wants to start working through the amino acids one by one I'm not going to say they should be stopped; sincerest good luck to them. I'm just not going to be the one funding it. > You could solve all forms of cancer tomorrow, which would be a great thing, but you aren't "saving humanity". This is a straw man. "Saving humanity", whatever that means, is outside the scope of medicine and I never argued for it. Nobody did. It isn't relevant.

tchalla 3mo ago

I’ve been hearing for 10 years now on how “AI” will change this clinical rate. It’s now like the “This is the year of Linux” prediction meme. And like Derek has mentioned multiple times you can’t statiscialise biology. I don’t think many people get it so we have tech bros like us throw AI at data.

Fomite 3mo ago
I've been hearing some form of it since I was an undergrad. I just submitted by packet for full professor. There have been some spectacular strides, but we've been through multiple rounds of "Stand aside, the computers will take it from here."
asdff 3mo ago
People saying this stuff aren't in the game. ML has been used in clinical research for basically as long as various ML methods have been around. Basically a century now in other words. AI leaders are trying to get money from people who don't understand the methodology such as investors or trump administration officials. Imagine trying to convince people who actually work day in day out with classic ml and deep learning to use your llm goobly goop bot.
- tchalla 3mo ago
  Yeah ML is used in clinical research but the narrative right now is that "AI" will take a target, find a molecule and we will magically have a safe drug in 3 years instead of 12 years. At best, it misunderstands biology and chemistry. At worst, it's one of those tech bro reductive statements. Even today, I am on a newsletter that has said AI drug will pass clinical trial in 2022 ... 23 .. 24 .. 25. Even the candidates that they talk about are mostly just repurposing. Don't get me wrong, ML has a solid place in clinical research but not like this.

Fomite 3mo ago

Doing hard things is hard.

arjie 3mo ago

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 gestation, so we try harder if they’re earlier than we would before. We should expect a homeostatic equilibrium between our skill and our ambition.

s1artibartfast 3mo ago
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 patients are alive 7 years out. Or Keytruda where 50% of advanced melenoma patients appear functionally cured 10 years post treatment.
- bonsai_spool 3mo ago
  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.

Plasmoid 3mo ago

The author, Derek Lowe, also writes the hilarious Things I won't work with series (https://www.science.org/content/blog-post/things-i-won-t-work-dioxygen-difluoride https://www.science.org/content/blog-post/things-i-won-t-wor...)

refurb 3mo ago

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.

mmooss 3mo ago
It's interesting that you frame it as the FDA increasing regulation and not that science has increased its foreknowledge of problems.
- refurb 3mo ago
  It’s a similar problem you see with all safety related decisions - as the large risks are eliminated you become more concerned about the smaller risks. Plenty of successful drugs from the 50’s had hERG activity, yet the impact on safety was marginal. Today plenty of programs are killed over it. Increase safety scrutiny does increase safety, but at a cost.
  - mmooss 3mo ago
    > Plenty of successful drugs from the 50’s had hERG activity, yet the impact on safety was marginal. Is there some evidence of these two claims? Obviously many experts think otherwise.
    - refurb 3mo ago
      Lots of examples of older drugs currently in use that are potent hERG inhibitors: haloperidol (antipsychotic), ketoconazole (antifungal), erythromycin (antibiotic), domperidone (anti-emetic), hydroxychloroquine (anti-malarial). All of these are rather potent hERG inhibitors, yet were approved and widely used before that activity was discovered. Pulling them off the market would have been quite disruptive considering some of them are the only effective treatment for rather serious diseases. Of course it's a matter of opinion, but I would argue some of these workhorse medications would have had their program killed by the manufacturer (fear the FDA won't approve) or the FDA itself (risk of fatal arrhythmias) if they were developed today. Yet the risk is managed by flagging the contraindication when combined with other drugs (since the inhibition is often additive).

_3u10 3mo ago

Umm restaurants ARE like that, why do you think there’s so many burger and pizza joints?

deleted 3mo ago
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pinkmuffinere 3mo ago

> But let’s think about that 91% failure rate for a moment. When I bring this up in presentations, I invite the audience to consider what the auto industry would look like of 91% of new car designs proved unable to roll out of the factory, or if 91% of new airliner models were unable to leave the ground - and if you only found that out after spending all the R&D money to build them at full size and trying to fly them. No cutting-edge restaurant could survive if 91% of its innovative dishes proved inedible or outright poisonous. What other industries operate under these bizarre conditions? This is bizarre, bordering on stupid. Frist of all, there likely is ~90% failure rate of prototypes; I feel that roughly matches my experience in engineering. Of course the design that makes it through the process, testing, refinement, and into mass production is not going to have a 90% failure rate, but that's a _finished product_, whereas clinical tests are just that -- tests. Finished cars are more analogous to individual pills coming out of the factory. And I'm not even sure the analogy would be very meaningful anyways, because we have different requirements for things of different impact and importance. A 10% manufacturing defect rate is fine in forks, but not for fire extinguishers.

fabian2k 3mo ago
A large part of that failure rate is in phase 3. Your comparison with prototypes would be more like drug development before even phase 1. Phase 3 is enormously expensive, much more than the earlier parts. And what's even worse, you don't get to learn all that much from failures in drug development in many cases. You can't just fix the problem and try again, you essentially have to try a completely new molecule.
- pinkmuffinere 3mo ago
  That's fair, phase 3 testing isn't an early prototype, it's a prototype with many years of effort behind it. But I still think it is _more_ like a prototype than it is like a product coming off an assembly line. Perhaps phase 3 is like the latest prototype from boom (the company trying to bring back super-sonic jets). Those prototypes represent 100s of engineering-years put together, and are not much like the prototypes you'd encounter in consumer product development. I still think 90% failure rate is believable for that. How many significant design iterations has Boom gone through so far? I don't really know, but I could believe it's been 10 significant iterations.

asdff 3mo ago

You want high failure rates. If failure rates were low, that tells you that you are probably being far too conservative in funding new clinical trials.

contubernio 3mo ago

Without doing any serious thought, it is concerning that the statistic doesn't vary more temporally. It seems too consistent, and raises the suspicion that it reflects regulatory agenda more than anything intrinsic

akk0 3mo ago
Going from an 80% to a 90% failure rate means the success rate halved; that's a pretty big change in my book.

L-four 3mo ago

If failure rates went down wouldn't that increase the number of clinical trials until the failure rates go back up.

qsera 3mo ago

>So when we do get something to work and something that people are willing to pay money for, we try to squeeze every dollar out of it because we never know when the next one will come along. Would make a small correction. It does not have to be people. It can be also be "doctors" or "governments". It is easier to convince or coerce/fool a lesser number of humans (doctors) or a single government regulatory body than to fool/convince every one who use the product, because the people can directly evaluate the product. And when a single doctor is coerced, then the product is forced on hundreds of their patients. When a government is coerced, then the product is forced on tens of millions of people..

akk0 3mo ago
Doctors are people
- qsera 3mo ago
  But they are not the one paying for the drugs they prescribe...

mbnielsen 3mo ago

Many comments so far seem to try to handwave away the 90 % failure as somehow "optimal" in the system, which seems absurd to me. It is clearly not advantageous for individual companies to keep a drug candidate alive long enough for it to fail in stage III or IV. One obvious question is why they don't and it is very, very tempting to speculate that it's because the problems are getting harder, we are targeting novel mechanisms etc. Again, I think this misses a simpler explanation: As with many cases where companies make seemingly bad decisions, I think a lot of the explanation lies in system dynamics. Think about the incentive structure inside large pharma companies - it is generally not a career advancement move for a project manager to kill the drug candidate they oversee. It is career advancing to get it approved for the next stage. What could possibly go wrong in this world?

rwmj 3mo ago
Sure, but Pharma A is full of career managers who never kill drugs under development and Upstart B relentlessly culls drugs that don't work early on. Upstart B's failure rate at the final stages is under 50% so they develop 5 times as many drugs, beating the existing company, and indeed all other drug companies. Since this isn't happening, it seems this might not be the explanation.
- ozim 3mo ago
  For me it seems this simplification falls flat right away when you take into account budget constraints. It is not software development where you can start a project every month see how it goes and drop it or pivot. I guess they use a lot of computer aided models before they even start serious parts but I believe this discussion is not about failure rates on that stage because then it would be 99%
logicchains 3mo ago
The human body is an extremely complex system. Simulating it completely accuracy would require a computer many orders of magnitude more powerful than anything currently existing, so the only way to know if a treatment doesn't produce any unexpected side effect is years of empirical testing, because such things can take years to manifest. Fundamentally the problem space contains inescapable complexity; it's not the fault of pharma firms.

braiamp 3mo ago

I had to look what "clinical failure rate" means and I think I got the answer in this paper [1] and... I'm not going to say that it is worrisome. Unlike other industries, we can't accurately model in the pre-prototype phase how something will behave in living beings. And to use the author examples, cars and airliners are big and way simpler to model than the complex pathways that you find in biology. We are chipping away at that problem but it's not like we have it mostly solved as other engineering areas of knowledge. I would argue that due that phase I successes isn't the benchmark, but phase II success should be the actual measure. I'm sure that if someone charts the accumulative success rate for each phase of clinical trials, you will see that phase I is the most brutal one. 1: https://www.nature.com/articles/nrd.2016.136 https://www.nature.com/articles/nrd.2016.136

officialchicken 3mo ago
> I had to look what "clinical failure rate" means That should have been the end if the comment; the follow-up by demonstrating such expertise just has me laughing.
- deleted 3mo ago
  [deleted]

timedude 3mo ago

This is no surprise. Read "Confessions of a Medical Heretic" https://www.amazon.com/Confessions-Medical-Heretic-Robert-Mendelsohn/dp/0809241315/ https://www.amazon.com/Confessions-Medical-Heretic-Robert-Me...

xvxvx 3mo ago

Animal rights campaigners like PETA have been saying this for decades: https://www.peta.org/issues/animals-used-for-experimentation/animals-used-experimentation-factsheets/animal-experiments-overview/ https://www.peta.org/issues/animals-used-for-experimentation... 110M+ animals suffering and dying for nothing each year. And people ask why I choose cruelty-free.

doadfda 3mo ago

[dead]

pmarreck 3mo ago

Finally, something that makes the current state of software development look GOOD!

tsoukase 3mo ago

Drug discovery and development is hard, unique and non comparable in the engineering world. It has it's own properties, like "the pipeline", I-... phases and a mere 20-year long patent duration (counting from molecule discovery). Imagine if after 20 years of it's inception on the paper the car's price falls 5-fold and you have to develop a new machine. The failure rate does not take into account the millions of molecules that are tested by various methods of protein folding or binding properties. The 90% remains stable with time because on one side an end product is more difficult to produce, on the other the technology of molecule discovery has improved in the same amount.

bibouthegreat 3mo ago

People get confused about all the types of clinical trials. The worst part happened in 1997 [1] Before this time, you could p-hack your studies. You could get a molecule and just look at some random effect that happens in any case because of sampling issues. Since 1997, you must register the full protocol to the FDA before the study. Since then, almost no study with a full protocol brought a really new medicine. [1] https://en.wikipedia.org/wiki/Food_and_Drug_Administration_Modernization_Act_of_1997 https://en.wikipedia.org/wiki/Food_and_Drug_Administration_M...

tim333 3mo ago

>It’s a nerve-wracking way to live, but there’s no alternative in sight. There's always AI simulation on the way. Deepmind's Isomorphic labs is working on it https://www.isomorphiclabs.com/articles/the-isomorphic-labs-drug-design-engine-unlocks-a-new-frontier https://www.isomorphiclabs.com/articles/the-isomorphic-labs-... And an AI designed drug for idiopathic pulmonary fibrosis from Insilico Medicine is going to clinical trials https://www.artificialintelligence-news.com/news/insilico-medicine-advances-ai-drug-for-ipf-to-phase-iii-trials/ https://www.artificialintelligence-news.com/news/insilico-me...

alan-crowe 3mo ago

People with serious illnesses long to get on to a clinical trial, hoping to get the latest and best treatment, even before it is approved. But it is not really like that. Only one phase III drug in ten really helps. And what of the other nine? Derek Lowe doesn't go into the downside, so I'm left to guess that eight out of ten do neither good nor harm and one in ten get their trial stopped in a panic when they turn out to be harmful. By all means volunteer for a clinical trial as an altruistic act, hoping to advance science and confer a benefit on those who come after. With such a high failure rate, the expected benefit is likely net zero.

maerF0x0 3mo ago

In addition to many others commenting that a great defense is to reject a lot of things. But also it strikes me, perhaps we're also approaching the limits of "drugs" as in compounds delivered by topical, oral ingestion, injectable etc? Perhaps the human creature needs upgrades that go beyond "just add chemicals systemically"? I'm thinking of things like targetted delivery by nanobots, gene editing, replacing body parts with engineered/mechanical versions... For example maybe we can obviate statins for those who have genetically high cholesterol by editing their genes, or maybe just replace the failing biological pump (heart) with a mechanical one? (Cue all the folks with the "One does not simply" memes :) )