| ▲ | EternalFury 12 hours ago |
| Anyone can mix chemicals in a test tube and claim it’s the cure for something. That’s the easy part. Proving it’s safe and effective, that’s what requires a lot of capital expenditure. This statement is a drastic characterization, but you could say “half a dozen PhDs can form reasons to believe they may have found a cure for something”, and the paragraph would end the same. |
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| ▲ | ramraj07 7 hours ago | parent | next [-] |
| Got my PhD from a lab that works on antibody drugs, they eventually even released one to the market. I’d argue that our current system is broken. There’s no reliable metric of drug effectiveness in any of our pre-clinical models, and thus we end up going into clinical trials quite blind indeed. And more often than not, what drug gets into trials has more to do with ego and politics than actual scientific merit. And the folks involved in these types of activities are (IMO) the most unoriginal types I’ve ever seen. There’s a lot we can do to improve our drug development process. It really doesn’t need to cost billions to bring a drug to the market. But the odds are stacked against anyone with a contrarian hypothesis and I just figured I’d save my sweat and leave this field instead. |
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| ▲ | mft_ an hour ago | parent | next [-] | | It doesn’t (have to) cost billions to bring a (successful) drug to market. And if you pick a single successful example that was discovered in academia, was spun out into a small focussed biotech, and was in a disease area that didn’t require large or multiple studies to make it to market, you’ll have your anecdote to prove your point. Except… you’d be ignoring the costs of the 90% of drugs that fail in phase 1. You’d be ignoring the huge amount spent on discovery across the industry that never leads to a successful candidate. Drug discovery and development is difficult because, for all of our clever science, it’s still essentially serendipitous and random. And we’ve not yet figured out how to make a production line out of something that’s random, try as we might. And it’s expensive because of the failures as well as the cost associated with success. | |
| ▲ | DrScientist 5 hours ago | parent | prev | next [-] | | I'd agree with a lot of that in terms of both many drugs being 'discovered' in clinical trials as oppose to earlier ( a lot of it it about choosing the right patients and dose ), and the differences in mindsets between researchers and those often involved in the clinical trial side. One of the things you've missed is the strong restrictions put on pharma in terms of promoting use of existing drugs beyond the existing approval ( which makes sense ), and the almost complete freedom Doctors have to do what they want - they can just decide to prescribe something off-label if they think it might help. It can take a very long time for new ideas to become new products - and a lot of that is inertia ( nobody else is doing it ). | | |
| ▲ | raxxorraxor 5 hours ago | parent [-] | | I think the restrictions on pharma, while doctors have more freedom is quite helpful. There are some problems here as well where this freedom has been abused, but overall that isn't a problem in my opinion. Clinical trials are long and expensive, the medical advisory board wants compensation as well. But even startups can theoretically fund new therapies if they and their medial advisory boards get subsidies. It is a lot of risk though because for most drugs or medical devices, the real effectiveness can only be determined later in the trial itself. |
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| ▲ | JPLeRouzic 4 hours ago | parent | prev | next [-] | | Many thanks for saying what I suspected when looking at the research publications and clinical trials on neurodegenerative diseases. I was starting to think I was an unproductive perpetual malcontent. For example, memantine has been tested 5 times in ALS. There even no pre-clinical studies that show any positive effect of memantine in animal models. This seems so bizarre to me. | | |
| ▲ | pfisherman 2 hours ago | parent [-] | | How good are our animal models of ALS? Are they predictive of effectiveness in humans? | | |
| ▲ | JPLeRouzic 2 hours ago | parent [-] | | I am not an expert (I am a retired R&D telecom engineer) but here is my take: * As for cancer, there are several (many?) ALS variants. The first gene to be associated with ALS was SOD1 G93A allele in 1993. It stayed the only ALS gene known until 2006. That was a curse for research as ALS with SOD1 origin is less than 2% of total cases, and even for SOD1 there are dozens of mutations associated with ALS, some with 6 months of life expectancy, others with 20 years. * Most commercial animal models are SOD1 G93A mice [0]. The G93A mutation represents roughly only 0.4-1.4% of all ALS cases worldwide, yet it is the most used animal model! SOD1 G93A ALS models are also the less costly animal models. * I think another important thing is that ALS starts often in hands (split hand phenomena) and targets skeletal muscles. But humans' nervous system for hands is very special, only shared with other upper primates. Other mammals like mice have an interneuron between the upper and lower motor neuron for hands. We do not, there is a direct connection between upper and lower motor neurons, reflecting the importance of manipulation for humans. Therefore for me, we can't prove with mice at pre-clinical stage, that a drug is efficacious or not (many drugs have some efficacy in animal models, but none in humans). * Some publications pretend they can use individual cells, fishes, or nematodes as animal models. That's laughable, it's ignoring the importance of anatomy and physiology. We are complex animals, our hormones, our immune system, and our metabolism are important to understanding ALS. The proof of that is that ALS patients who have the best life expectancy have a BMI of 27. * Other publications pretend to make their own animal models with some chemical, like BMAA, a neurotoxin found in certain cyanobacteria. Those publications smell bad behavior for me. If you want to buy a mice model of ALS: [0] https://www.jax.org/jax-mice-and-services/preclinical-resear... |
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| ▲ | evantbyrne an hour ago | parent | prev | next [-] | | Some drugs not being able to make it into phase 1 clinical trials sounds like a functioning regulatory system to me. The bar isn't astronomically high for a phase 1. Like sure, you can't just do it in your garage like a web startup, but there are reasons for that. If anything, there are way too many drugs floating around in LDT right now, hence why those are being faded out. | |
| ▲ | prox 5 hours ago | parent | prev | next [-] | | Is this a market that can be disrupted? It sounds if you know how to save a few billion and introduce more science based drugs, it’s ripe for an overtake. | | |
| ▲ | DrScientist 5 hours ago | parent | next [-] | | In the same way Uber disrupted licensed taxis - or the big internet firms disrupted ad supported media. ie totally ignoring existing regulations, pretending they don't apply to you and just hoping you can push through. In a lot of the 'problems' are the regulations ( which are double edged and tricky to get right ) - and pharma companies are just following the rules. I think governments might be less lax in letting there be a new wildwest in drug development. | | |
| ▲ | llamaimperative 4 hours ago | parent | next [-] | | Pointing the finger at regulation is misleading IMO. The regulations for bringing a drug to market are essentially quite simple: prove that it’s better than what currently exists. What makes it difficult is the word “prove” It turns out it’s obscenely hard to make a drug that’s good, and even harder to prove that it’s good. | | |
| ▲ | DrScientist 4 hours ago | parent [-] | | > prove that it’s better than what currently exists. So how do you do that ethically? How do you justify taking off something that you know works to some extent and try something completely new or worse placebo? ie don't you have to construct the trial in the context of existing treatments etc? These are the kind of challenges that makes drug development slow - in the end you don't do one trial, but a series of trials, slowly building confidence and making the case. Often that's what takes the time during the clinical phase. Of course it would be much faster to go straight to a big trial that would show how well your treatment works in conditions optimal to it - however that kind of 'move-fast break-things' approach involves potentially breaking things which happen to be people. Regulation just reflects the cautious 'first do no harm' philosophy. Now let's be honest - big pharma will simultaneous complain about regulation and the cost of development, and at the same time know it creates barriers to entry - there is always some frustration about the slowest of regulatory authorities to adopt new methods - however you wouldn't want your regulatory to be gungho. | | |
| ▲ | rflrob an hour ago | parent | next [-] | | > or worse placebo Just to be clear, most drug trials for anything where we have an effective treatment are not “new drug vs placebo”, but instead “new drug vs standard of care”. Thus the goal being to prove it’s better than what already exists. | | |
| ▲ | DrScientist 5 minutes ago | parent [-] | | Sure - it rather depends on how good the 'standard of care' is or how much consensus there is on what that should actually be. If the standard of care is already good and you don't need a placebo - then you have another problem - you probably are going to have to do quite a big trial to get the stats to show a significant difference, and you are going to find it harder to persuade people to participate with an experimental treatment if there already is a fairly good treatment. The whole point about the challenges with clinical trials is that it's not an intellectual exercise in designing the perfect experiment and 'just doing it'. It's about persuading yourself, the regulators, the doctors and ultimately the patients that it's something you should try - and before you've done your first trial you don't have any human data to show it's safe and effective - all a bit chicken and egg - the solution is often to move slowly in stages. |
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| ▲ | datavirtue 2 hours ago | parent | prev [-] | | Inmates. Go wild. For some reason this abhores the intellegencia while myriads of innocent rodents get tortured. | | |
| ▲ | wat10000 an hour ago | parent | next [-] | | Sorry, are you having difficulty with the concept that human prisoners should have more rights than mice? | |
| ▲ | DrScientist 2 hours ago | parent | prev [-] | | Purdue Pharma, fentanyl and doctors abrogating responsibility for patient safety is an example of 'go wild'. On your second point - I'd agree that a lot of animal experiments are not that informative - but lets be clear 'clinical trials' are simply experiments on people. I'm not sure I'd want to give Musk, Zuckerberg or Bezos free reign to experiment on desperate people in the medical space. Depends on whether you treat people as just grist to your money making mill - or perhaps you think the ends justify the means? |
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| ▲ | jorvi 2 hours ago | parent | prev | next [-] | | Uber disrupted taxis because taxis were a sleazy experience, with dirty old cars, “broken” meters and rude drivers that tried to get you to pay extortionate prices if they knew you were in a pinch. Stop trying to venerate the taxi industry, they’re horrible. | | |
| ▲ | DrScientist 19 minutes ago | parent [-] | | I think that depends on what part of the world you live in. My experience of taxi companies in the UK is that they are generally safe, reliable and operate based on reputation. My experience of taxi's in the US is that they appear to be often operated by desperate people living on the edge of existence. |
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| ▲ | adventured 2 hours ago | parent | prev [-] | | There's no hoping you can push through. The US Government has complete top-down control over the sale of prescription drugs in the US, from clinicals to approval to distribution & sale. The sole reason Uber pulled off what they did, is there's no national authority governing taxi style services for all states and cities, it's a state and local effort. So Uber counted on navigating around zillions of slow local governments long enough to get big, and it worked very well. You can't do that in prescription drugs, the feds have a big hammer and can (and will) use it anytime they like. |
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| ▲ | ramraj07 5 hours ago | parent | prev [-] | | Absolutely, and if you recall, even YC tried to get in on this idea. Except they did the same mistake anyone who comes up with this disruption plan commits (including Google with Calico, or Zuck with CZI) - they recruit existing academics to do the disruption. Unfortunately this just fails miserably because they’re culturally corrupted to think of standard dogmas (like there can never be a single cure for cancer). I remember a time when other such dogmas existed (remember how it was considered impossible to de-differentiate somatic cells?). The other mistake tech bros make in biology is they think they can make any cool idea work if they are smart enough. Because this is actually true in tech. But biology is restricted by laws of nature. If a drug doesn’t work, it can’t be made to work. There’s no room for wishful thinking. Third mistake I see often is individual bias towards fields that they come from. Someone who has an RNA background will only try to use RNA to solve everything, likewise with antibodies, or imaging, etc. The current research funding system incentivizes such thinking and it becomes entrenched in anyone already in this field. There’s never a thought of “which is the exact technology and approach I should use to solve this problem independent of what I’m an expert at?” So a lot of projects are doomed from the start. As long as you’re cognizant of these three facts, I think it’s very possible to disrupt this field. | | |
| ▲ | nradov 2 hours ago | parent [-] | | Is there any plausible biological reason to think that there could ever be a single cure for cancer? | | |
| ▲ | ckemere 2 hours ago | parent [-] | | Perhaps immune-based therapies like CAR-T are based on the premise that there are many cancerous cells in your body all the time, but your immune system deals with them, and it’s only when it fails to do so that you end up in the pathological state. So the “single cure” is the normally-functioning immune system? | | |
| ▲ | nradov an hour ago | parent [-] | | That might be part of it. And yet sometimes people with normally-functioning immune systems also get cancer. So while that might be an effective treatment for some patients it's not going to be a universal cure. |
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| ▲ | pfdietz 4 hours ago | parent | prev [-] | | The current system is like Churchill's description of democracy: the worst system, except for all the others. Biology is extremely complex. There's no substitute for actually trying things out on subjects in vivo. For many diseases we don't even know the cause (Alzheimer's for example). Drug companies have all the incentive in the world to improve the system to get better odds; it's not like they want drug discovery to be such a crapshoot. | | |
| ▲ | clooless 38 minutes ago | parent [-] | | We also don't understand how some drugs work, either (e.g. Tylenol). | | |
| ▲ | pfdietz 9 minutes ago | parent [-] | | A utility-maximizing drug discovery system would, I think, devote some effort to biological experimentation on healthy humans, giving them chemical probes to see how that affected their biology. As is, ethics requires we get this information accidentally, for example from that famous recreational drug chemist who gave himself Parkinson's Disease with a botched synthesis that made a highly neurotoxic chemical. And some of the information comes from drug trials. A useful drug is not the only value obtained from a drug trial -- each trial is also a test of a hypothesis about the mechanisms of a disease. One of the books of the "Colossus" trilogy (about a computer that takes over the world) had the computer doing this sort of medical experimentation on randomly selected drafted subjects, with the idea of maximizing overall utility. It shows the problem with utility maximization as a goal, similar to the requirement that people give up a healthy kidney if someone else needs a transplant. |
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| ▲ | null08 8 hours ago | parent | prev | next [-] |
| This article is about a phase III RCT that the hospital managed to do without major industry capital injection. This truly was a major achievement (I have been involved in a phase III RCT myself). It was published in the New England recently: https://www.nejm.org/doi/full/10.1056/NEJMoa2402604 |
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| ▲ | kijalo 8 hours ago | parent | next [-] | | This trial is using an existing drug in a potentially novel way (before surgery as opposed to after surgery). I dont think it really lives up the original article title. | |
| ▲ | refurb 5 hours ago | parent | prev | next [-] | | The article literally says "Funded by Bristol Myers Squibb and others". | |
| ▲ | Gokevin 7 hours ago | parent | prev [-] | | Supported by Bristol Myers Squibb; |
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| ▲ | TheToadKnows 37 minutes ago | parent | prev | next [-] |
| Drug development faces a forecasting problem, not a measurement problem. In the same way that temperature, pressure, and humidity readings have been collected for centuries, it wasn’t until we developed models and computational power that accurate weather forecasting became possible. Similarly, in drug development, we’ve long had access to extensive pre-clinical data and measurement tools. However, without predictive models to interpret this data, we will continue to struggle to forecast a drug’s safety and effectiveness in humans. Interesting coincidence that for the last several decades, the rate of success of a drug advancing from a phase 1 clinical trial to approval is about 10%, which was just about how good we were at forecasting tomorrow’s weather between 1900-1950. |
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| ▲ | ano-ther 9 hours ago | parent | prev | next [-] |
| From the article translation it sounds like they have phase 3 data and submitted or are about to submit an application to the European Medicines Agency. That means they have gone all the way to prove it’s safe and effective, and now have to convince the regulators. Can anyone find the studies? |
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| ▲ | InDubioProRubio 9 hours ago | parent | prev | next [-] |
| Does it? There is a billion people on this planet without adequate medical system - whose health is not considered worth investing into. If they get auto-diagnosed by app (zero-cost), they could volunteer for a free chemical trial (delivery of package), a application of said package (local nurse - not free) and a series of follow up scans + analysis. The office behemoths involved are optional. Whats missing is tools to scan the body locally for cheap. The rest can be automated or distributed to people with an interest in success (high-level-analysis by the cure developers). Here are the volunteers: https://www.sciencedirect.com/science/article/pii/S266700542... |
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| ▲ | wesselbindt 4 hours ago | parent | next [-] | | > whose health is not considered worth investing into. If they get auto-diagnosed by app (zero-cost), they could volunteer for a free chemical trial What a profoundly ineffective and broken system we have that this could be uttered as anything other than satire. | | |
| ▲ | InDubioProRubio an hour ago | parent | next [-] | | PS: Yes, its a deeply broken system- and its also on the point where the well-off blue blooded caste starts to blame the lower-classes for the misery inflicted upon them again- aka, if you are of low blood, you are obviously lazy because you spend so much time in bed being sick. Ideology can be a very effective tool to deactivate compassion. | |
| ▲ | InDubioProRubio 3 hours ago | parent | prev [-] | | So the perfect nothing is allowed to block the imperfect something, because we wait for humans to transcend to angelic beeings? | | |
| ▲ | nkrisc 2 hours ago | parent | next [-] | | I’m inclined to believe that the status quo is actually better than mass human experimentation on the poor. | |
| ▲ | wesselbindt 2 hours ago | parent | prev [-] | | Yeah, not doing human testing on poor folks without a choice is really "angelic" and "perfect". Very high bar to set, how could we possibly achieve such high standards of morality? | | |
| ▲ | InDubioProRubio an hour ago | parent [-] | | They have a choice. To use the medicine or not. The choice is gone in the other case- where you can die of cancer for "ethical" comission reasons. | | |
| ▲ | jodleif an hour ago | parent [-] | | That’s essentially a non-choice. Also data of self-administration is probably worthless. |
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| ▲ | llamaimperative 4 hours ago | parent | prev [-] | | Lovely: so just give tons of people an experimental drug and collect garbage data by doing so! | | |
| ▲ | bilbo0s 4 hours ago | parent [-] | | I'm not sure people fully understand the scientific method. All data is not reliable data. |
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| ▲ | cchi_co 10 hours ago | parent | prev | next [-] |
| Discovery is just the tip of the iceberg |
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| ▲ | refurb 6 hours ago | parent | prev | next [-] |
| Exactly. I work in this field. Doing phase 3 clinical trials costs between $5,000 to $20,000 per patient per year. This particular drug did a phase 3 with 423 patients for 2 years, so you're looking at a cost of $4M to $16M just for this one trial alone. Then add on top all the CMC (manufacturing) research that needs to happen, the regulatory filing work, etc, etc. Unless someone has a few hundreds of millions sitting around, you aren't bringing a novel drug to market without external funding. |
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| ▲ | yread 5 hours ago | parent [-] | | When hospitals are contracted to do work in a clinical trial setting they take their costs and multiply it by 10 (at least). This was done in house with in house resources. This hospital has its own pharmacy that can synthesize drugs and give it to the patients. The pharmacy probably charged just the material costs internally and not for the time. |
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| ▲ | vasco 10 hours ago | parent | prev [-] |
| Since these are cancer trials I'm assuming no test subjects get paid, and university PhDs research for free, like in every other field, so what necessarily has to be expensive about it? If you have to pay 200 homeless to take your 0.0001% better than placebo antidepressants in the context of a huge corporation, and maybe redo the trial a few times, I can see how that gets expensive, but I don't see why it's a de facto rule. But even the big trials it's weird how expensive people say they are. Most other products require a lot of high paid labor to produce, think of a video game studio for example, also without any guarantee it won't flop, and it certainly takes longer to develop than to do a clinical trial. |
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| ▲ | robertlagrant 6 hours ago | parent | next [-] | | > Most other products require a lot of high paid labor to produce, think of a video game studio for example, also without any guarantee it won't flop, and it certainly takes longer to develop than to do a clinical trial. You have to try really hard to make a video game no-one wants[0]. You might not recoup all your investment, but you won't sell zero copies. A drug can have all that money poured in, and nothing come of it. [0] https://arstechnica.com/gaming/2024/09/two-weeks-after-launc... | | | |
| ▲ | rahkiin 9 hours ago | parent | prev | next [-] | | PhD candidates are paid salary in the Netherlands. Less of course than the senior trial researchers at pharma. I also would not assume there is no compensation for subjects as thats part of the medical-ethical process and not just ‘it helps the subject so no money’. | | |
| ▲ | vasco 9 hours ago | parent [-] | | The €30k to €35k per year they make in this context approximates to free. Any normal company has to pay much more than that for less. A non-phd software engineer will get paid much more to change button colors for example. So that can't be the reason they are expensive and a PhD candidate is doing many other things than just helping to run trials. | | |
| ▲ | JPLeRouzic 8 hours ago | parent | next [-] | | > Any normal company has to pay much more than that for less In most EU countries, the employee receives much less than what they cost the employer. In France, if an employee gets 30K euros, the employer has to provision ~45K Euros. | | |
| ▲ | vasco 7 hours ago | parent [-] | | What's your point? I've lived in 3 different european countries, I'm familiar with fully loaded costs, I don't see how social security changes anything. By paying more for less I mean PhDs candidates are very cheap labor for what they bring to the table. |
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| ▲ | StefanBatory an hour ago | parent | prev [-] | | Also as much as it pains to say, 30-35k Euro is high salary there. :( |
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| ▲ | monero-xmr 8 hours ago | parent | prev [-] | | This is the most misinformed unknowing take in all of the comments. You can’t just recruit “200 homeless” and have it pass research standards. The homeless population is the most difficult of all to track, maintain accurate records, and even recruit for that matter. You think the homeless just line up for novel drug trials and report back for updates on a strict schedule? You need good candidates for the trial. You need them to follow up. You need admins to properly track them and ensure it’s at least mostly accurate. Even the best trial candidates won’t follow the protocol correctly. | | |
| ▲ | vasco 6 hours ago | parent | next [-] | | I invite you to read https://www.researchgate.net/profile/Carl-Elliott/publicatio... If you genuinely think the medical and pharma industry don't exploit homeless and other marginalized populations out the wazoo as lab rats. They also only stopped doing it to prisioners when it was made illegal, because that's what they did before. Of course using them has a lot of practical problems, as you outline, other than the much bigger ethical issue. You managed to miss the whole point of the comment though. Which is, how is it possible that a multibillion dollar industry, exploiting both the test subjects AS WELL as the researchers in the form of practically free PhD candidates can still claim it's one of the most dificult / expensive endeavours? Where does the money go? When you look, it goes to the bureocrats and to the "bio-investors". | |
| ▲ | 8 hours ago | parent | prev | next [-] | | [deleted] | |
| ▲ | pfdietz 2 hours ago | parent | prev [-] | | I (not homeless!) was recently in a vaccine trial (Moderna's mRNA vaccine for RSV). The trial paid me $100 per office visit, just to show up. There were periodic phone checkups ($50) and a weekly status check through an app ($10). I did follow the protocol pretty damn well. There was an incentive to come in and get checked when symptoms occurred, including when I came down with COVID at one point after a trip to Europe. |
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