Comment by pezzana | Hacker News Reader

Comment by pezzana | Hacker News Reader

> Pfizer’s phase 2/3 trial randomized non-hospitalized adult COVID-19 patients who were at high risk of progressing to severe illness to receive placebo or Paxlovid, a combination of the protease inhibitors PF-07321332 and ritonavir. The efficacy analysis is based on 1,219 patients.

One noteworthy feature is the newness of this drug:

> PF-07321332 was developed from scratch during the current pandemic. It’s a reversible covalent inhibitor that reacts with one of the main protease’s cysteine residues. Owen [director of medicinal chemistry at Pfizer] also discussed the chemistry involved in scaling up the compound. The first 7 mg of the compound were synthesized in late July 2020. Encouraged by the early biological data, the Pfizer team aimed to scale up the synthesis. By late October, they’d made 100 g of the compound. Just two weeks later, the chemists had scaled up the synthesis to more than 1 kg. Owen said 210 researchers had worked on the project.

https://cen.acs.org/acs-news/acs-meeting-news/Pfizer-unveils...

Less than two years from lab to clinic is highly unusual. If approved, I believe this would be the fastest lab-to-approval for a small molecule drug in the history of the FDA.

>Less than two years from lab to clinic is highly unusual.

I assume like most other COVID vaccines/treatments, the timeline is shrunk by going straight to more expensive phases of the trial instead of having preliminary ones of escalating cost and confidence. Or at least prepping for them.

For instance, all the vaccines started setting up commercial production around the same time they started trials, because it's not worth the months delay of setting up a production line to determine if it worked first.

Also one factor slowing some studies has been the need to wait for test cases: you can't infect people with, say, Ebola so you need to wait for enough people in your study cohort to contract it naturally to get enough data to say whether a vaccine candidate is having an impact. During a pandemic, it's sadly easy to hit a statistically-significant number of infections.

This has interesting implications when we consider how much money drug companies “should” be paid for inventing important new life-saving medicines.

I frequently hear/read complaints of "that's outrageous [that this medicine costs $X]!"

Well, maybe it is; maybe it isn't, but if you make sure it costs $X/100, I can be pretty sure you'll get less drug R&D.

Pharma companies in the US spend about twice as much on advertising as they do on R&D [1]. Recent data compiled by the House Oversight Committee shows the biggest pharma companies spent $56 billion more on stock buybacks and dividends than they did on R&D over the past five years [2]. Very little of the ridiculous prices that US citizens pay for medicine (directly or via insurance) actually goes towards R&D.

[1] https://journals.plos.org/plosmedicine/article?id=10.1371/jo...

[2] https://oversight.house.gov/sites/democrats.oversight.house....

Your first link is from 2008, and analyzes data from 2004. I don't see how this proves anything, or even suggests much, about the industry today.

Your second link shows that the pharma companies spend almost as much on R&D as on stock dividends and buybacks. Is there any other industry that spends as much on R&D? Apple, for instance, seems to be spending ~6x as much on stock buybacks and dividends as on R&D (approximately, based on the first Google hits).

Even your own links contradict your claim that very little goes to R&D.

This is not a dick measuring contest. The comment was challenging the notion that pharmaceuticals companies spending the majority of their cash on advertising and stock buybacks is a desired outcome. The specific numbers, especially across industries, are meaningless.

Advertising includes drug samples given to doctors, which many/most of them give to patients who can't afford said drugs.

How many of them are you willing to cut off?

In order to make the drug more affordable? I mean... all of them? Maybe I'm not understanding your point?

Those free samples very much make treatment less affordable. They don’t need to hand out samples when their treatment is the only option, they need to advertise to out compete generics.

It’s shockingly effective, look at say prescriptions for patented opioids vs the vast numbers of equally effective generics. Doctors are extremely susceptible to advertising just like most people, the difference is it’s not their money being spent.

In the case of doctors it's more high-touch than plain old ads anyway. The representative stops by and chats them up, maybe they get some sponsored continuing education (which is of course designed to push expensive products), etc.

And the reps are often smoking hot, so docs don't mind making a bit of time for conversation.

Fun fact: Female secretaries (or other "gatekeepers") are less likely to let hot female sales people back to the doctor.

Huh? Per unit dispensing of generic opioids dwarfs branded opioids.

“Clinical studies comparing the response and side effects of various opioids have not been able to show robust differences between drugs.”

So, it’s not a question of which is prescribed more, it’s a question of why branded opioids are ever prescribed. We aren’t talking about a ~100 Billion dollars of accidental waste, it took a lot of work to extract that from the general public.

I mean the biggest opioid sales were OxyContin and the argument there was the time release which wasn’t available in a generic.

As a part of my job I’ve talked to insurance companies and they aren’t willing to pay for branded pain relief drugs unless there is some differentiating value.

https://www.fda.gov/drugs/information-drug-class/timeline-se...

1987 “May: MS Contin, (morphine sulfate) approved; first formulation of an opioid pain medicine that allowed dosing every 12 hours instead of every 4 to 6 hours.”

1990 “August: Duragesic (fentanyl transdermal system) approved; first formulation of an opioid pain medicine in a patch (sometimes referred to as a “skin patch”) that is changed every 3 days.”

1995 “December: OxyContin (oxycodone controlled-release) approved; first formulation of oxycodone that allowed dosing every 12 hours instead of every 4 to 6 hours.”

I find myself very skeptical that "free samples of really expensive drugs given to indigent patients" constitute very much of the budget there.

BS, doctors give the samples to friends and family, and some to patients. Doctors can't know a patient is poor. In private practice, the doctor assumes the patient isn't poor.

Doctors usually pretty well know which patients are poor based on how they dress and speak.

As an alternative, you could have a single payer, public health care option that would be significantly cheaper than the current shit show that the US system has (modulo the small percentage of Americans who have had a genuinely positive experience with the syst as opposed to the Kafkaesque nightmares that are the more common take.)

All of them. Having some drugs laying around and handing them out as medication is wildly irresponsible

That's not how it works. The doctor prescribes the drug and gives the patient the free sample. What, did you think they were in a "take one" candy jar?

Free samples over R&D? In what world does that sound... sound?

Terrible take. Your first source vaguely tries to estimate promotional spending (not advertising as you deceitfully claim). Promotional spend has a positive ROI (or you wouldn’t do it). So spending $1B in promotion gets your $1B+ in sales (it’s self funding).

Plus stock buybacks and dividends are being criticized? Returning money to investors is “bad”? Who do you think provides capital for drug development? The Grenadier Guards?

$1B in R&D can often result in $100B in sales, so it is "even more" self-funding.

“Don’t tell me where your priorities are. Show me where you spend your money and I’ll tell you what they are.” – James W. Frick

Are you claiming that Pharma companies don't want to make money and are therefore not investing more in R&D?

Price is not defined by costs. You adjust prices for maximum profit, as in the k of (h,k) of a quadratic equation.

If you can produce a drug for 1$ a dose and you can sell it for 100$ at most without losing customers, you do that.

If your product costs are too high, you don't advertise. You sell the drug to the government as an "orphan drug".

Price very much depends on cost, the goal is profit maximization not maximizing revenue.

Suppose you can sell 1 million sandwiches at 5$ or 1/2 a million at 6$ which you price depends on your cost of production. If it’s costing you less than 4$ you pick the first option if it’s more than 4$ and less than 6$ you pick the second. Though in the real world costs aren’t independent of sales so it’s even more complicated.

It’s only when you get extreme markups from a guaranteed monopoly that you can approximate things as revenue maximization. Also, drug R&D numbers are extremely inflated as among other things it’s got tax advantages.

You got me on taxes. I totally left that out.

My whole post is the exception you mention in your third paragraph. Your first paragraph is what happens when you have generics, and they start treating the drug more like a sandwich that a treatment. (No bioequivalence tests, safety concerns, etc)

Sure but how many drugs get pitched that also cost $1 billion to find out that they were bog useless and had to be tossed in the garbage.

But does it really increase sales? We’re talking drugs that are prescribed by a doctor. Or do people not buy and take their statins unless they see a tv ad?

Probably because the people will name-drop that particular brand. It's up to the doctor to responsibly prescribe it, whom probably heard of the drug because of other forms of marketing or flat out kickbacks

I mean, cancer drugs are regularly advertised.

That should scare everyone and I’m not sure why it doesn’t. They wouldn’t be advertising them if it didn’t increase sales, which probably means oncologists aren’t always prescribing what’s best.

As far as other medications, most people don’t go to the doctor regularly. Even if they did, they would probably need to inquire about their condition to have the doctor think of updating anything.

As someone who has worked with doctors for much of my career I can assure you the quality of doctors varies just as much as other professions.

I remember having to personally call a doctor and ask them to stop prescribing a drug because it was pretty much malpractice to not use the newer approved drug from another company.

A positive ROI in isolation for one company doesn't necessarily mean anything useful is gained across the whole industry. Consider what would happen if promotional spend was just taking market share from other pharma companies - it'd be wasted money, but everyone would have to do it to preserve market share.

> Promotional spend has a positive ROI (or you wouldn’t do it).

That's incorrect; promotional spend on prescription drugs is the globally suboptimal result of a prisoner's dilemma where the prosecutors are going around saying "hey, that guy over there snitched, so should you". There is absolutely no guarantee that ROI is positive.

> Who do you think provides capital for drug development? The Grenadier Guards?

Most of basic drug development happens in labs e.g. at universities that are funded mainly by public sources.

Per the latest PhRMA member survey, drug companies spent about $13 billion per year on preclinical R&D, which was about 15% of their total R&D spend. Meanwhile the NIH alone provides about $40 billion per year for preclinical research. So funding for actually finding new drugs and therapies is dominated by other funding sources than drug companies.

If you look at e.g. Pfizer and J&J, more than 85% of their revenue comes from drugs that were invented elsewhere. Just to clarify, I'm not saying clinical trials isn't a necessary and expensive thing. But in large part it's not developing drugs, it's checking that there are no big side effects and that efficacy remains what you saw at small sample sizes.

For instance mRNA vaccines were invented in publically funded laboratories. Monoclonal antibodies that work against inflammation is another example. And of course CRISPR, which is very promising.

Very little drug development happens in academia. You are missing all the time, money spent in public and private markets in the biotech ecosystem that Pharma largely is the back end buyer for through off-balance sheet acquisitions/deals. VCs collectively spend tens a billions a year on biotech (~40B this year), and much more in public markets (IPOs and secondary public finances).

In the example you bring up. Moderna raised and spent billions over a decade since it was founded on the 'academic invention', and didn't have a product until their vaccine. The same is true for BioNTech. There was a large chance these companies could have folded, and before the pandemic, most were deeply skeptical.

R&D is actually usually done outside of the major drug companies and is funded by the government. So I doubt it really will effect it. And most price hikes lately have been in pre-existing drugs.

It's interesting to note that the Pfizer, AstroZeneca and J&J vaccines were all invented by 3rd parties.

Early stage R&D is the part that typically happens outside of big pharma, though all the big companies have their own proprietary early stage efforts/portfolios.

Even then govt funded stuff is mostly preclinical. Start ups mostly cover anything from animal studies to phase 1 / 2.

Late stage R&D, manufacturing, and marketing is extremely capital intensive and complex and is mostly done by large pharma companies, who either license the asset or enter some sort of partnership with the IP holder. And I am including regulatory approval, demonstrating value to payers, etc under marketing (e.g. it is not just advertising).

That's fine for new drugs.

Not for generic drugs.

And let us buy our meds out of country.

(And buying out generic drug manufactures should other drug companies in order to decrease competition is not cool either.)

It's not really this simple since you can directly subsidize/incentivize R&D if that's the goal.

> I can be pretty sure you'll get less drug R&D.

You'd get more R&D. There were way more new drugs released before Bayh-Dole.

Maybe not. Most of the low hanging fruit. It's becoming much more difficult to find novel small molecule drugs. The possibilities are finite.

And that was due to the wisdom of operation warpspeed. Trump is under credited for this (whether his idea or not, he could claim it as such). What’s shocking to me is that he hasn’t been more pro-vax given we have the vaccines we do because of his administration.

Operation Warp Speed is, to me, an indication of the power of government "intertia". Trump changed a lot of things, and while an uncomfortable amount of the U.S. government seems to run on "tradition" that isn't actually law, after 4 years of unchecked assault it was only at the very end that it really got crazy.

Warp speed is the work of career guys. Not even Fauchi -- he was important, but these ideas are put together, presented, and executed by the unknown 9-to-5ers.

> Operation Warp Speed is, to me, an indication of the power of government "intertia".

We call this the Deep State

I find this whole deep state thing very strange. It's meant to sound ominous, but really it's just a bunch of career diplomates that have worked over many administrations who are the ones that make anything that works, work. We should be doing our best to preserve their knowledge and capability.

It's not meant to sound ominous. It's a phrase that's been coopted.

No need to use a conspiracy theory name for it.

The truth is that any government needs a ton of people to operate properly and you can't change all of them upon election.

Actually, scratch that, you can sort of do that every election/change of government.

Do you know where they do that? Failed states. Failed states change most if not all the government employees upon regime change, to put people from the new regime in their place.

It's an unmitigated disaster, because you also need people other than politicians to do the heavy lifting. And those skills can't always be built up over just 4 years, you need more than that. It's dumb to throw them away. Let alone the fact that changing them with the regime means that it's super unlikely you keep the competent people, you just get new loyal folks.

It's not really a conspiracy theory though, it's just the reality that much/most of the power of the government is in the hands of unelected bureaucrats. That doesn't imply the bureaucrats are conspiring.

And that's not necessarily a bad thing (for the reasons you describe) but there's a fundamental deceit going on if the president can't actually control that bureaucracy (because people assume that he can).

> We call this the Deep State

If by “we” you mean fans of the arbitrary, irresponsible, corrupt patronage-based governance of the spoils system who use the term to denigrate the idea of a professional civil service with loyalty that extends beyond the person of the current chief executive on whom their tenure depends, then, sure, “we” do.

Stable Western nations have career bureaucrats that continue working their office regardless of which political party is at helm. This brings expertise and continuity and has nothing to do with deep state. A new minister will assign new goals but retain the old team that has the best understanding available in their specific field.

>What’s shocking to me is that he hasn’t been more pro-vax given we have the vaccines we do because of his administration.

He made vaccinations a partisan wedge issue to such a degree that he can't afford to walk back from it if he wants to run again in 2024, similar to the Republicans' former position on Obamacare.

That seems a bit revisionist. To my knowledge, Donald Trump was always a vocal supporter of the Covid vaccine. Kamala Harris and Joe Biden were the ones sowing doubt about it - right up until they won the election. Harris, in particular, described Trump as irresponsible for advocating for Project Warpspeed and suggesting that people should take a Covid vaccine before it had gone through the full approval process.

I think you may be getting their personal stances confused with the partisan arguments about vaccine mandates that have evolved in the year since.

Trump didn’t make the vaccine a wedge issue, he made COVID a wedge issue by repeatedly calling it a political lie (which resulted in vaccines becoming a wedge issue).

I suspect the confusion between your perspective and that of the previous commenter is a result of the difficulty Trump experienced in trying to promote a vaccine for an illness he was himself at the same time claiming does not exist.

He also clung to and promoted a bunch of other unproven treatments leading up to the vaccine… why should anyone have trusted him by this point in the pandemic?

I think he was recently boo'd at a rally because he told people to get vaccinated.

Warp Speed had nothing to do with this.

Pfizer/BioNTech weren’t part of Warp Speed. And the Oxford/AstraZeneca vaccines were ready and had begun trials before they were part of Warp speed.

The only vaccine it might have had an impact on was potentially Moderna. But even Moderna had the vaccine ready well before the Trump administration even believed that the virus did not only affect Chinese people.

Finally, Warp Speed was not a brilliant new idea they came up with. It was part of the pandemic response plan the Obama administration had prepared many years ago. The difference is that if they had actually followed the plan warp speed would have been activated well before.

Pretty much the only thing that the Trump administration can be uniquely credited for is picking the name. Which, as we can see from the fact that the majority of current vaccine skeptics are worried about the speed at which the vaccines were created, was a terrible choice for a name.

The Latest article in BMJ about the failures in scientific integrity in the pfizer trials are a likely consequence of your last paragraph I would guess.

Can you provide a link to that?

https://www.bmj.com/content/375/bmj.n2635

It's not uncommon for human tragedies to serve as a backdrop for significant scientific progress.

Wars and pandemics seem to be the testbeds for medicine, where people are desperate enough to try anything, and legislation is relaxed accordingly. The biotech companies know this all too well, and take advantage when the opportunity arises.

Development tools help accelerate software development. Better tools help you go faster. This is happening in biotech as well - they're getting some very good development tools.

Is anyone familiar how this scaling up process works? To what point can it be scaled up using lab methods, and at which point does it make sense to start making it large-scale?

There was an article specifically which explained that about remdesivir in really clear language but apparently it isn't there anymore.

Here's a scholarly article on the evolution of synthesis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340098/

Is the similiarity of COVID-19 to other coronaviruses also a speed up? We are not starting from complete scratch in that case.

Aren't we? I thought that until SARS the scientific consensus was that coronaviruses are not interesting. And SARS died out too quickly to achieve much. But I might have not paid enough attention.

I’m pretty sure the reason Moderna was able to develop a vaccine so quickly (Feb 2020?) was because they already knew the spike protein to target from the original SARS outbreak.

This is something I haven't encountered before in biochemistry

"reversible covalent"

A chemical covalent bond. Maybe it means something else in this article?

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