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.
Clinical failure rates over the decades: yikes
131–140 of 146 posts
Re: Clinical failure rates over the decades: yikes
#132Earlier quoted context omitted.
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.
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 prototy…
Phase I testing is ~$5M. Phase II $6-20M. Phase III is $10-50M. https://pubmed.ncbi.nlm.nih.gov/26908540/ (up to 2012 numbers, non-inflation-adjusted)
Those costs are strictly for the mandatory testing, not the precursor drug design, etc.
The cost and calendar time required to be sunk before 10% pay off is why you generally only have drug development done by (a) some of the largest corporations in the world or (b) fly-by-night companies hoping to sell their preliminary drugs/results to the former to complete testing.
Re: Clinical failure rates over the decades: yikes
#133Earlier quoted context omitted.
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.
> 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.
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).
Re: Clinical failure rates over the decades: yikes
#134> 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…
It's not that much better in plant breeding: You'll find hundreds upon hundreds of supposedly better varieties tried, and 5 years later, you are lucky to get 1 good one that one would consider commercializing. And that's after years of testing changes in smaller settings. We just don't have models that are predictive enough without planting, and waiting for plants to grow takes time.
(This is your annual reminder that atomic gardening is a thing. https://en.wikipedia.org/wiki/Atomic_gardening)
Re: Clinical failure rates over the decades: yikes
#135Earlier quoted context omitted.
I dont know why you are being rude about a topic you know nothing about. As some who actually does this for a career, they are largely correct. Dose frequency and side effects especially are major reasons. I would add route of administration and patient convenience as well. Anti-vegf treatments for blindness are a good example if you want to research. They all have basicly the same effect in terms of letters preserve…
Not being rude, and I definitely know about medicine. I explained in sibling that I understood the Lowe article to be about new research (as a researcher, I don't often think about how hard it is to make a GLP survive the stomach but I do think about how incretin biology works). I guess these VEGF agents you list feel like a very straightforward engineering question (can we make an antibody that targets VEGF, humaniz…
Oh fun trivia about those straightforward engineering problems was Novartis beavu. It had a few percent higher Side Effects than standard of care after lunch. This was enough to cause Novartis (a top 5 or 10 Pharma company) to essentially cease all ocular drug research and sell off much of their ocular portfolio.
Re: Clinical failure rates over the decades: yikes
#136Earlier quoted context omitted.
This is very facile thinking - are there any examples of a-e in the real world (namely, a brand new drug program was spun up to exploit a-e) ? I think not, which is why I asked the question.
I dont know why you are being rude about a topic you know nothing about. As some who actually does this for a career, they are largely correct. Dose frequency and side effects especially are major reasons. I would add route of administration and patient convenience as well. Anti-vegf treatments for blindness are a good example if you want to research. They all have basicly the same effect in terms of letters preserve…
To add a somewhat cynical view, a significant part of the original motivation for the ranibizumab (Lucentis) development was due to pricing arbitrage across diseases. bevicizumab was priced based on uses in cancer indications with a “large” volume (many mls) used for systemic infusion. The same product injected into the eye, in say a 1:1000 volume, could be efficacious for AMD, but pricing per volume would be trivial amount at the bevi cost per volume. So they tweaked the active ingredient to a new product (exact same mechanism ) and raised the price per volume to a market standard cost per treatment. There may be some pk-type benefits to the derivative , but the pricing context is an industry case study.
Re: Clinical failure rates over the decades: yikes
#137Earlier quoted context omitted.
I dont know why you are being rude about a topic you know nothing about. As some who actually does this for a career, they are largely correct. Dose frequency and side effects especially are major reasons. I would add route of administration and patient convenience as well. Anti-vegf treatments for blindness are a good example if you want to research. They all have basicly the same effect in terms of letters preserve…
To add a somewhat cynical view, a significant part of the original motivation for the ranibizumab (Lucentis) development was due to pricing arbitrage across diseases. bevicizumab was priced based on uses in cancer indications with a “large” volume (many mls) used for systemic infusion. The same product injected into the eye, in say a 1:1000 volume, could be efficacious for AMD, but pricing per volume would be trivial…
Yeah, I think that's especially relevant here too and reinforces the phenomenon where US hcps will opt for the best independent of price, even if the marginal benefit is vanishingly small or hypothetical/not data driven.
Some providers did opt to self-compound avastin for off label use mostly in Europe but also in the US.
The idea that Pharma companies would pass on developing a product 1% better than keytruda, or that hcps would pass on buying is laughable
Re: Clinical failure rates over the decades: yikes
#138Earlier quoted context omitted.
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 prototy…
Phase I testing is ~$5M. Phase II $6-20M. Phase III is $10-50M. https://pubmed.ncbi.nlm.nih.gov/26908540/ (up to 2012 numbers, non-inflation-adjusted) Those costs are strictly for the mandatory testing, not the precursor drug design, etc. The cost and calendar time required to be sunk before 10% pay off is why you generally only have drug development done by (a) some of the largest corporations in the world or (b) fl…
tl;dr -- Boom's iterations are very similar to a phase III trial! Please prove me wrong!
Just to clarify, I think our numbers are in agreement here. From your numbers, phase I + II + III would be in the range $21-75M, all told. Let's double that to account for inflation (2012 is quite stale), to get $42-150M. In California, I'm going to estimate a "normal" engineer's compensation is $150-400k, and the company actually pays more than this because of benefits, HR, etc -- call it $250-600k. Let's say it's 350k fully loaded on average. Then the $42-150M number represents 120-430 engineer years. I'd totally believe that Boom has 120-400 engineers working full time, so if they make a major revision every year, then each major revision is like a full phase I-III progression!
I think there's some reverse-dunning-kruger going on in this thread, where because we're all engineers we think engineering is comparably easy. My claim is that it's actually pretty similar to medical testing, in terms of generic human effort (to the extent that can even be measured and quantified).
edit: According to wikipedia, Boom had 150 employees in 2021 [1]! I'm very proud of my estimate lol, it seems like it was right on the nose. Somebody give me a prize!
Re: Clinical failure rates over the decades: yikes
#139In 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 :) )
Re: Clinical failure rates over the decades: yikes
#140Earlier quoted context omitted.
"Why would anyone make a drug if the current prevalent treatment was as good as a functional cure?" I am not sure whether you ask for economic why, or an overall why. The overall why seems easier to explain: a. The new drug may be cheaper. b. The new drug may be safer. (e.g. no risk of anaphylaxis etc.) c. The new drug may not need cold storage (huge problem outside the First World). d. The new drug may have other pr…
This is very facile thinking - are there any examples of a-e in the real world (namely, a brand new drug program was spun up to exploit a-e) ? I think not, which is why I asked the question.
You could compare ibuprofen and naproxen. One lasts 4-ish hours while the other, having different functionality, lasts 12-ish hours.