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?
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?
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 properties that the original does not have (e.g. being taken once a day instead of four times a day, not requiring people to stay off specific food etc.)
e. The side effects (such as vomiting) may be lower.
In general, it is always better to have alternatives in medicine.
And frankly your comment about "facile thinking" is totally unwelcome. Have you seen someone vomiting their guts out after chemo? That is torture.
Oncology is one field where every less punishing treatment would be useful. Some patients have to be taken off otherwise life-saving treatments because they cannot tolerate them. That is true even with well-treatable cancers such as Hodgkins, which 90+ per cent of patients survive.
The search for different formulations of an active agent seems a little unrelated (sibling comment to yours) but I concede that I didn't exclude that in my earlier argument.
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My point is that several posters here are giving arguments from first principles ('yes of course we would want to keep trying to make more medications because more options is better than fewer options') but not engaging with the enormous cost such a rationale would entail.
And the notorious inhaled insulin that Pfizer launch (and horribly failed).
There are many ways to differentiate drugs, not just efficacy.
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 preserved on an eye chart if dosed as perscribled.
It's a 15 billion dollar per year Market that resolves on the basis of the longest dose interval and side effects.
You can look at the bevicizumab, to ranibizumab, to aflibercept, to brolucizumab, to faricimab drug programs. There are also dozens of failed programs in this area and perpetually new drugs and Gene Therapies looking to break into the market.
Perhaps an even more salient example would be pill based GLPs looking exploit the listed factors
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, humanize its Fc etc) while Lowe brings up conceptual areas like PCSK9, HMG-CoA reductase.
I still maintain that the 1% better thing is not going to lead to incredible success because rational actors aren't going to change their prescribing patterns each time a new agent gets approved.
They want the best, and are willing to sepnd 10x the price or switch treatment to secure that 1% survival, extra week of dosing interval, or the ability to inject at home via mail instead of some sweaty infusion clinic.
I used to think like you before transitioning from medical devices to pharmaceutical development.
The USA is the only real Market that matters for drug development. Unlike the with marginal benefit pricing and National negotiation, the US market is consumer Centric, with patients and their providers wanting the best, even if it is marginal. That 1% means that you can either take the market share or 10x the price.
> I guess these VEGF agents you list feel like a very straightforward engineering question
Each of those straightforward engineering questions takes about 100,000 labor-years and a billion dollars to get approval.
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
The new drug could be cheaper to manufacture, fewer side effects, a full cure in stead of a functional cure.
How will your clinical trial of the ostensible full cure work if standard of care is curing people?
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.
Both models and methods are challenging. Biology is hard.
Who isn't digging in exactly?
Pharmaceuticals are more than a two trillion dollar market with Millions of scientists and engineers and doctors working diligently to refine the process.
There's tens of billions of dollars to gain for any company that comes up with even minor improvements to success rate.
Keep in mind that we’re talking about the success rate of the last step in the process: human trials. For every human trial there were millions of drug candidates that were considered and rejected. Tens of thousands of those candidates were actually synthesized and tested in animal models or in cell cultures. In the 80s these numbers were all lower. Back then only thousands of candidates would be considered, and only hundreds would be synthesized for actual testing.
Worse, for every candidate that gets to the human trial stage there were multiple projects that rejected all of their candidates and were discontinued. The numbers here are pretty vague, but past surveys have found that the number of failures at this stage is really high too, maybe as high as 90%.
Pharma companies are hardly unaware of this problem. They regularly spend years (even decades) and hundreds of millions of dollars on drug projects that never reach human trials. They spend even more on the ones that reach human trials and then fail. As a result they have spent billions on new methods, new systems, new techniques, etc, all intended to reduce that risk. It appears that all they have managed to do is keep pace with the increasing difficulty of drug development.
I don’t necessarily agree that this is inevitable, but it is understandable.
> The most parsimonious explanation is either our models or methods (or both) are garbage.
I disagree with that. In spite of the difficulties we have managed to get around 50 new drugs approved every year for the last several decades. Sometimes more, sometimes less, of course, but as far as I know there’s been no obvious trend upwards or downwards. That doesn’t seem like garbage to me.
> If the goal were flight, would jumping off cliffs with wings like birds be “ambitious”?
Not any more, no, but it was quite ambitious back in the 1890s. Back then there was a single scholarly study on the lift generated by wings, and it was completely wrong. The Wright brothers built their own wind tunnel and ran their own tests to get reliable data to base the Flyer’s wings on.
If you’re talking about copycat mechanisms, that is fine but we’re still left discussing successes when OP is about failures
You spend the 1 billion for a ticket to win 30 billion/yr for the next several years.
Is it rational to spend 1$ to make $100 10% of the time? A 99% failure rate would be break even.
You can spend that $1B to win a new category or that same money to maybe be non-inferior to Keytruda, but maybe fail. I think copycat design does happen, but I mostly notice it when drugs are being developed simultaneously at different firms. Perhaps it happens more beyond this, I'm unsure.
Otherwise, it makes more sense to try to find an indication where you are approved and have no competition.
I'm not talking about biosimilars or strict copycats.
Completely novel indications are a tiny portion of Pharma development.
Lucrative and technologically viable untreated indications are few and far between.
Meanwhile, you have huge proven markets for treatments that impact millions of people with corresponding Revenue.
If you are skeptical, you can simply go look at the development Pipelines for the top 10 pharmaceutical Giants and see how many of their new programs are for indications with existing treatments versus orphan.
In recent years, approximately one-third of all novel new drugs approved annually by the FDA have carried a Breakthrough Therapy Designation. This corresponds to drugs that claim a substantial improvement over the standard of care for their target disease.