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.
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.
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.
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.
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.
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.
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.
We can't do any of that for drugs that affect emotions and consciousness because we're barely in the stone age of our understanding of the brain and the technology we have to affect it.
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.
Stop trying to venerate the taxi industry, they’re horrible.
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.
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.
Bat "normal" might be. Of course, now we are crossing the threshold from medicine to bio-augmentation.
There won't be any magic for cancer. It's just going to be slow grind to solve one hard problem after another.
Also, you seem to be very pessimistic. Many interventions in the history of medicine, like washing hands or the first vaccine against smallpox, were almost "magical" in their efficiency: they addressed a lot of problems through a relatively trivial intervention.
It is likely that a lot of this low-hanging fruit has been picked up, but you insinuate that there isn't any low-hanging fruit to begin with, only an endless slog of attacking hard problems. That is way too negative.
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 ).
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.
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.
* 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...
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.
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.
And “biology is complex” is the type of truism I hinted at. You can always say that whenever you fail. Biology is complex and Alzheimer’s is the most complex of them all, to be sure, but I hope you’re aware of the. Alzheimer’s cabal allegations that the entire field was mutilated by a bunch of people into believing and pursuing the wrong hypotheses for decades.
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.
I wonder if the "optimal" theory is portfolio in this case, or if there is a new generation of VC/pharma investors who want a higher probability at a lower return.
> you’d be ignoring the costs of the 90% of drugs that fail in phase 1
It depends on what you call "bringing a drug to market".
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* Phase I costs little, around $1M during the trial, and involves only a small group of participants (one or two dozen people), so it's not multi-center and it is manageable by a few people at a biotech. The problem is that most phase I trials fail, but this is not an issue of cost, it's an issue of the way it is decided as explained by ramraj07, another commenter.
Too often it is started on a hunch without solid pre-clinical data, sometimes it is because the drug was tested and failed in another disease and the managers "pivoted" to a new disease because then it costs little to try again, sometimes it's just a "weird IP/financial trick" where you combine an existing drug and an unrelated drug. Then you know you have a relatively efficacious drug, no need for toxicity studies and you can patent it.
On the contrary, many trials could be done on drugs with good pre-clinical data, but that does not happen because it would be hard to patent.
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* A phase III costs around $25M for one or two hundred participants during the trial [0]. It lasts 6 months at most.
Some publications cite much higher numbers (~$1G), but this does not make sense as drugs are often developed by biotechs (startups, in other words) with only a few million in their pockets.
Another cost inflationary cause is subcontracting to CROs, as most biotechs do not have the manpower, knowledge and business connections to conduct the trial.
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* Once a drug receives commercialization authorization, a major company usually buys the rights and then starts the marketing phase. This starts with teaching doctors on how to prescribe and administer the drug. It means publishing articles in the mainstream medical press, inviting doctors to conferences and workshops, and paying medical sales representatives.
It is costly, this is probably where are spend the ~$500M but for me, this is not drug development costs, it's just marketing costs.
[0] http://idei.fr/sites/default/files/medias/doc/conf/pha/conf_...
Phase I: a small biotech I know of in oncology has phase I costs in the order of $500,000 per patient; this is a higher-end cost, due to their sites being in the US (more expensive than Europe) and because as a small biotech they're had to outsource virtually every aspect of running the trial. In big pharma, per-patient costs were more like $70-100k per patient, but this was just the pure money paid patient (to the site, and external costs like drug supply and shipping) and ignored the cost of laboratory, clinical, operations, and data management work that was being done in house. All told, it would typically be hard to get even a phase I study completed for less than 10x your estimate, and this is before you consider any additional recruitment needed between dose escalation and phase III.
Phase III: again it depends on many factors, but in big pharma a trial cost of $100-200k per patient was again not unreasonable, and typical phase III trials where you're comparing to a meaningful established medicine are larger than 100-200 patients. A biotech I know of is unable to run a phase III for a promising drug without finding a partner to support the majority of the cost (which is >100m EUR in oncology) and they're not wasting money.
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A less anecdotal approach is to consider the total R&D costs of companies across a given timescale, and divide by the number of successes. It's a pretty old reference too, but Matthew Herper did this in 2013. [0] Yes, there were some outliers with low costs, but you'd have to understand the details for context. The typical costs were in the hunderes of millions to billions per successful drug.
[0] https://www.forbes.com/sites/matthewherper/2013/08/11/the-co...
Yet you seem to have assumed I’m oblivious to the reality when I’ve already pressed I’ve been in the deep end and am aware.
I’ve already given an explanation on why I don’t agree with “its still serendipitous and random” - the people working on it are not smart enough and are more interested in stoking egos and careers than doing real science, even if they’re capable of doing so.
“90% of the drugs fail in phase I” - why are you telling me that when I’ve already given an explanation on why that is so - we don’t have good preclinical models that correlate with drug effectiveness - is it that you didn’t understand what I wrote, or are also neck deep in this cultural quagmire you refuse to acknowledge it?
Maybe the one area we would significantly disagree is that I don't think it's simply that "the people working on it are not smart enough and are more interested in stoking egos and careers than doing real science".
Honestly, I've had discussions with so many mid-level smart trusted colleagues who always think that the higher-ups are making stupid decisions, and they'd do better. They're right that some of the decisions might be stupid (and you're probably right about "stoking egos and careers") some of the time, but people are promoted, decision-makers come and go, and the decisions (and failure rates) don't really improve. I (think I) see it for what it is, and agree that we lack meaningfully informative pre-clinical models, but I'm also comfortable to acknowledge the weaknesses of the system and be honest that I don't have all of the answers. At the moment, it's a heinously inefficient crap-shoot, but it's the best we've so far come up with.
But, prove me wrong. There are likely countless molecules that have been discarded that have therapeutic benefit waiting to be realised. (I don't mean to sound facetious here but) If you can do better, and are smarter than and will make better decisions than everyone else in the industry, you'll be a billionaire in short order, as this is literally the golden ticket in this industry that everyone else is missing.
I have done my PhD, I need to take a break to actually take care of my family and immigration. I hope to get back to this field at some point, in my own terms, and see if I can succeed. If it works, it works! If not Who cares right! Let's see.
That being said, we're talking about human lives either way so it needs to be thought through and avoid unintended disasters through lack of care.
The correct New England paper about this treatment is here:
https://www.nejm.org/doi/10.1056/NEJMoa2210233
This one is TIL therapy, where you basically take tumor-infiltrating lymphocyte from the patient, stimulate them ex vivo, and put them back.
The reason this is so impressive -- and highlighted by this article -- is that large phase III trials like this have now become so complicated due to various technical, financial, logistic, ethical, and above all regulatory challenges, that they are now mostly done by companies, or at least as joint ventures with companies (and often in jurisdictions with less of these issues, certainly not in the EU like this one). It is very, very impressive to pull off something like this as an academic institution (at least in Europe). What's more, the funding came from KWF (the Dutch cancer foundation), which is actually a public charity that mainly relies on donations.
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.
Drug production is very different from the typical work done in a hospital pharmacy.
https://www.avl.nl/en/preparing-for-your-appointment/departm...
https://www.avl.nl/en/preparing-for-your-appointment/departm...
https://www.nki.nl/research/facilities-platforms/bioanalytic...
They aren't manufacturing any medicines in those pharmacies. They are buying final product and then preparing it for administration.
GLP and GMP certified don't mean they are manufacturing. GLP are lab best practices and GMP is manufacturing, but it covers a lot of ground, so a basic pharmacy can be GMP and all they do is prepare sterile product.
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?
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.
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...
All data is not reliable data.
What a profoundly ineffective and broken system we have that this could be uttered as anything other than satire.
Step 2: Offer them the “choice” of possibly receiving care by being medical guinea pigs for those who created the situation that deprived them of medical care in the first place.
A coerced choice is a not a free choice.
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.
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.
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.
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".
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...