> If you could do research that will save 10 lives, vs research that will save 1 life, which would you choose?

Both. We're not even close to our limits on research capacity.

If we actually were at the limits of research capacity, and we were actually forced to make decisions between livesaving treatments to research where we couldn't do both without sacrificing something else that saves lives, then yes, of course, choose the thing with the highest number of predicted lives saved. But we're not even close to needing to make such decisions yet.

We just don't have a good system for funding cures you can't sell to millions. That's not anywhere close to "heartbreaking decisions" territory; that's "societal coordination problem" territory.

> We just don't have a good system for funding cures you can't sell to millions

(Full disclosure: close family member works at $bigPharma)

I don't think it's about finding treatments you can "sell to millions", it's that in pharma, like in pretty much every other business, it's about ROI.

You definitely don't need millions of patients, but you do need to cover the R&D costs _and_ have enough left over to keep the shareholders happy.

This is such a fucked up incentive structure. Literally having the capacity to save lives but not doing it because otherwise people will pull out their money because Roblox is has a better ROI.

> This is such a fucked up incentive structure [..]

It may well be(!), so let's assume you're right, what better incentive structure should we put in place instead?

Increase general taxation and use that to fund more pharamaceutical R&D?

Break up the pharma companies and let them only be at-cost (!) manufacturers, move all R&D off to universities, and cooperate with other countries in said R&D efforts.

> Break up the pharma companies

For many politicians that would be seen as a "courageous decision" (hat-tip: Sir Humphrey Appleby)

> and let them only be at-cost (!) manufacturers

Won't it be hard to find investors if you do that?

> move all R&D off to universities

I think the "D" in "R&D" might be the problem in this approach. Universities are great at many things, including research, but based on my experiences (science PhD two decades ago in a research group which worked on anti-infectives) the scientists there aren't necessarily very good - or even actually interested - in development as such. We partnered fairly closely with $bigPharma at the time, and they funded a fair chunk of our work.

> Won't it be hard to find investors if you do that?

Better that than paying negative interest for German 20 year bonds, if you ask me.

> Universities are great at many things, including research, but based on my experiences (science PhD two decades ago in a research group which worked on anti-infectives) the scientists there aren't necessarily very good - or even actually interested - in development as such. We partnered fairly closely with $bigPharma at the time, and they funded a fair chunk of our work.

Agreed, universities have historically not been involved into the development part. But that is not a given dogma that can't be changed - the government could fund the establishment of development departments.

Alternatively, international governments could establish cooperative efforts to develop pharmaceutical compounds. Rare diseases and the decline of available reserve antibiotics are a global problem affecting every country on Earth just the same.

Can you illustrate for a lay person the difference between research and development in pharma context?

Research = determining a candidate compound, e.g. a new antibiotic, (e.g. by taking and tweaking an existing compound, by basing off of the actual viral/bacterial genetic code such as with the Biontech/Moderna CoV vaccines or by isolating a compound found in a plant, fungus or other natural agent which has been determined to have the effect you want), and initial checking against cell cultures and/or lab animals for effectivity.

Development = taking a lot of candidate compounds and evaluating them in the classic three-stage procedure - phase 1: determine how the compound is processed in actual human bodies to check if it is actually safe to ingest and what side effects can already be observed (n ~ 20-80), phase 2: determine effective dosage (n ~ 100-500), phase 3: check effectivity in a double-blind trial (n ~ 1k-10k), as well as the fourth phase (after-license monitoring) [1][2].

The more a compound progresses, the more expensive the trials get to conduct, not just because the participants usually get some compensation for their risk, but also because all the data has to be tracked and processed. And a lot of candidate compounds fail somewhere along the path (either because they are ineffective or because the side effects are too severe), which makes the money invested effectively wasted (from a capitalist point of view, not from a scientific!).

[1]: https://en.wikipedia.org/wiki/Clinical_trial

[2]: https://studienteilnehmergesucht.de/ratgeber/die-vier-phasen...

> Development = taking a lot of candidate compounds

At least one $bigPharma defines "research" as being everything up to and including the first proof of concept in a human [Phase I] trial. After that would be "development".

That'll mean no more drug development.

My grandmother had rheumatoid arthritis, and it made her life utterly miserable for her last 10 years. Recently, Enbrel was developed by a biotech for profit company, it is the first effective treatment for rheumatoid arthritis.

No university or government came up with it. A for profit company did.

> Increase general taxation and use that to fund more pharamaceutical R&D?

Take the US military budget and give it to life saving research instead of life taking.

Edit: Also implement a wealth tax instead of income tax. Discourage hoarding of wealth and concentration of power in the hands of top 1%.

Ah yes so China or Russia can invade and establish a totalitarian regime. Excellent idea.

You don't have to give up all of it. The total budget of US is larger than the next 6 countries combined. India, which is actually surrounded by hostile neighbors, one of which is china manages to defend itself with a tenth of the budget. My guy you are giving military money they didn't even ask for in this year's budget. Please stop repeating this line. American budget it not to stop China or Russia, its to assert their own will on the world.

> The total budget of US is larger than the next 6 countries combined.

Not in % of gdp. The only metric that matters. The US economy is massive in size so of course the budget is a big number.

> one of which is china manages to defend itself with a tenth of the budget.

Everything is cheaper in China. You can do a lot more with one million there than in the US.

I don't know why you are talking about china while the point I was making was about India defending itself against china. Also indian % of GDP for military budget is 2.8 while for US its 3.75. US has no neighboring countries actively attacking it, India does.

edit: BTW, is there any actual proof that this whole military budget dissuades Russia and China in any way?

> This is such a fucked up incentive structure.

It has produced far, far better results than communist incentive structures.

> We're not even close to our limits on research capacity.

Maybe not at your stage of research, but it's my understanding that further down the pipeline (eg clinical trials) you're mich closer to the limits, simply due to financial constraints: given that a trial for something you can sell to millions isn't that mich more expensive than one you can sell to dozens,and given that you need to get payed for your job, i don't see how it doesn't make sense to prioritize the lower hanging fruit. Am i missing something?

Thanks for your answer. Yes, this is not a case of lacking science, research, or even treatment capabilities. It is a case of too many hoops to jump.

Maybe twenty years from now some people with a high degree of knowledge, skills, and some resources will be able to get around these hoops illegally (by the laws of certain jurisdictions) and fix these conditions (or kill themselves or somebody else trying, but so does god/nature and doctors, with different[citation needed] probability distributions).

> Both. We're not even close to our limits on research capacity.

Really? From the outside it seems to me like we are beyond our limits on research capacity.

The progress seems to be slowing down everywhere while the price per discovery of a new drug skyrockets with many having rather disappointing efficacy (high NNTs).

None of those limitations seem inherent, nor are we close to the societal limits for what we can do when we actually care about accomplishing something. We may be somewhat close to the limits of what we can do with current R&D structures and incentives, but that's quite different.

Major pharma companies are all constantly competing, and very often are duplicating work because they are not sharing major experimental results. The way it feels is that there's already "too many people" working in certain areas (e.g. in cancer), while almost no attention is paid to these rare diseases.

I think that more people studying rare diseases would result in a net gain of lives saved; I don't think it's as zero-sum as "either 1 person's life is saved or 10 are" in this instance.

Research also cross pollinates across disease areas. For example, understanding altered metabolism in cancer can yield insights for non-oncological metabolic disorders. Oftentimes, though, nobody's working on translating that work out of a cancer model, because the financial incentives are not there.

I wonder if you could run a pharma company that buys IP for failed cancer treatments and runs small trials in rare diseases. you have the advantage of having passed Phase I/II usually, so you know it's decently safe, and oncology hits a lot of diverse targets.

there are some examples, for instance enzastaurin being repurposed for vascular EDS, after washing out as an angiogenesis inhibitor for cancer. I don't know if it makes sense mechanistically, I sure hope it does.

On the other hand, competition has given us what, 6 covid vaccines of varying effectiveness, and in record time. What if only the least effective one was developed, and took 18 months?

The 1962 FDA effectiveness mandates have had the side effect of increasing drug development costs enormously, and that shuts down development of treatments for rare disorders.

I think the idea would have been that Pfizer and Moderna could have pooled resources and made a single optimal vaccine faster, though I'll admit I'm not sure it could have happened any faster than it did from my perspective.

The Kefauver Harris Amendment you refer to was immensely important towards the development of safe and efficacious drugs -- I do not see the connection between that act and rare disease therapeutic development. In fact, drugs that only offer marginal improvements in quality of life for rare genetic disease patients are often fast-tracked by the FDA. Requiring that a drug _works_ shouldn't inhibit drug development. Otherwise, we end up with tragedies like what happened with the use of thalidomide, which prompted this amendment in the first place.

Competition is an incredible driver of outcomes, e.g. moon landing. It's also better from a risk perspective since it decorrelates efforts and we only need 1 to succeed. It also allows evolution to operate, where the incompetent and broken and corrupt die off and the productive are given more resources, which tends to lead to overall improvement.

Sure, competition also creates waste, which is your main point here, but don't discount the upsides.

Competition has proven itself in the real world. Having only one monolithic vaccine maker (whether for-profit, non-profit, or government) would be a very bad thing. What would happen if it falls to corrupt leadership, as one of many examples of how this could go wrong? There is no mechanism to escape badness here, because we only have 1 of them.

It is possible to maintain the benefits of competition without the level of duplication and profit motives that we struggle with today.

Large scale collaborative scientific endavours like CERN show us that it is possible to both publically share knowledge and still explore multiple avenues and competing designs. There's also no financial profit motive and while CERN receives a lot of public funding, it has to pump that funding back into the economies of the funding countries so it serves more like a high-tech industry stimulus and technological incubator.

I see no reason why a similar aproach for the development of (specific) therapeutics could not work.

I agree that it's possible to preserve many of the benefits of competition under a more centralized and explicitly cooperative structure. You see this sometimes within large for-profit companies that have competing products, which are siloed from each other in the workplace. This works fine, because there is still a profit motive at work and the identical evolutionary forces that will kill a particular silo if it's underperforming, and the same competitive pressure to perform.

Much larger cooperative structures are less proven to work and are more hypothetical, though, even if CERN is an example of such a structure working. The risk, mainly, is that there isn't a good corrective mechanism if the whole thing becomes corrupted or rotten from the top. The other risk is that the cooperation is actually detrimental to progress because it correlates outcomes via group think. Some decorrelation is nice. I am happy that Musk et al. weren't forced to become cogs at NASA, and could explore their own ideas, which was easier to achieve by then being explicitly separate entities (even if they were reliant on contracts).

> This works fine, because there is still a profit motive at work and the identical evolutionary forces that will kill a particular silo if it's underperforming, and the same competitive pressure to perform.

the profit motive in a multinationally funded system is still there in the sense of 'we have a budget of X, what's the best way to spend it?'. And research avenues that fail to yield the expected results can be terminated. In my experience, disagreement between researchers or groups were also far from uncommon. But maybe that's just physicists being exceptionally knowitall^H^H^H hard to convince :)

It's not flawless, but I don't think it could be less efficient use of public money than the current system where we publically fund early research and the succesfull projects get snatched up by the industry, patented, and sold for large profits. Even if a lot of pharmaceutical research ends up going nowhere (or a competitor beats them to it), we still end up paying for it trough the profit margins of the parent companies.

Raising healthcare costs are a serious concern for many countries, and part pharmaceuticals are a non-trivial part of the cost. Researching and producing them locally might help reduce that cost and stimulate a broader healthcare industry.

I do fear that pharmaceutical research might be to politicized for a multinational approach(e.g. HIV, what disease to prioritize). And there's bound to be some backlash from certain groups over a large 'shadowy' multinational body doing human trials.

"Safety" is quite a wide concept. I heard a professional drug researcher say that aspirin wouldn't pass the trials today, and certainly not as an over-the-counter drug. Too many side effects.

If we can use a software analogy, mess like Windows 95 wouldn't see the light of the day. But they were useful nonetheless.

I'm beyond puzzled. The multiple COVID vaccines weren't developed so quickly because of competition. They were developed by an unprecedented worldwide effort and government support.

I’m not sure that history is going to be kind to Trump’s shortcutting[1] regulatory approval on the current vaccines.

[1] “Operation Warp Speed”

You don’t know in advance how many lives will be saved by research. You may not know what you are researching at first; diphenhydramine is a moderately effective sedative, but turned out to be a strong antihistamine.

> If you could do research that will save 10 lives, vs research that will save 1 life, which would you choose?

The diseases like what OP is dealing with are the ones that are going to advance science for all of us. That’s where gene therapies are going to be applied first which will pave the path for more mass-market treatments.

I first heard about her efforts when she donated $40M to UCF. https://www.ucf.edu/news/scott-40-million-transformational-i...

I hope we can get in touch somehow. Thank you.