470 Comments

It's interesting that the person in charge of the executive branch cannot direct or in any way influence the executive branch's decisions. You can argue that he shouldn't to preserve their integrity, but still it's interesting.

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Or Congress for that matter. They could amend whatever law says "it's illegal to distribute a drug that's not approved by the FDA" to say "it's illegal to distribute a drug other than Paxlovid that's not approved by the FDA", couldn't they? Hungary did something like this with Russian and Chinese COVID vaccines.

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I mean, Hungary didn't amend the law in this manner, but just changed the law governing how the FDA-equivalent is supposed to decide approvals in such a way that it effectively required it to approve those vaccines, which it did.

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Your photos get 4/5 from me

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Well, I think it is reassuring. Imagine the outcry if Trump had personally approved $drugname as COVID treatment. In the worst case the US drug market would be split into republican-approved and democratic-approved drugs...

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Imagine the studies that could be done!

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This is the right take. There are still a few areas of the government that the average person doesn't believe is in bed with one of the tribes. Could you imagine the distrust we would have on a grand scale if we lose that?

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If Biden strong-armed the FDA to approve paxlovid right now, that would (allegedly) save approximately 50,000 lives. I'm reluctant to kill 50,000 people in exchange for some nebulous notion of distrust.

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> some nebulous notion of distrust

The lack of trust in institutions has been real and had real-world damage done to the country.

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Exactly. The 50,000 people who are going to die if we don't push out Paxlovid are mostly dying due to institutional distrust. In September 1,800 people died a day and 90%+ of them were unvaccinated.

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I don't believe that figure is correct. It is difficult for me to find the numbers, since the CDC and others are reporting elusively in terms of death rates of the vaccinated vs unvaccinated, and I my numeric literacy is not enough to work out the actual figures.

So looking at September, if 1,800 people died, and the death rate for the vaccinated is 0.86 per 100,000 and the death rate for the unvaccinated is 11.51 per 100,000, and the US vaccination rate is 57.8%, how many of the 1,800 who died were vaccinated and how many were unvaccinated?

I don't think the answer is 180 vs 1,620, but I don't know.

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founding

There's nothing nebulous about the difference between high-trust and low-trust societies, and preserving social trust is definitely worth 50,000 lives. Whether the particular increment of social trust that would be burned by openly politicizing an FDA drug approval is valuable at that level is not obvious. But we've been burning an awful lot of social trust in this pandemic, mostly for the sake of hamfisted interventions that did little if any good. So I'm going to push back on "to hell with that namby-pamby 'social trust' thing, we're saving *lives* here!" when I see it.

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As opposed to the world we live in where Trump developed vaccines at "warp speed" and now Republicans strongly support those vaccines and don't spread anti-vaxx nonsense online.

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The main limitation on something like the capacity of the FDA is funding, and that's controlled by congress.

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I am not persuaded that designing cost effective regulations is much more costly than non-cost effective ones. I do not think funding explains failings in general and it sure does not explain Paxlovid.

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the FDA is funded by the drug companies- to the tune of approx. 45% of its budget. it has been this way since 1992.

Why is the FDA Funded in Part by the Companies It Regulates?

Nearly half the agency's budget now comes from 'user fees' paid by companies seeking approval for medical devices or drugs

source: https://today.uconn.edu/2021/05/why-is-the-fda-funded-in-part-by-the-companies-it-regulates-2/

relevant text:

"In 1992, in response to intense pressure, Congress passed the Prescription Drug User Fee Act. It was signed into law by President George H.W. Bush.

With the act, the FDA moved from a fully taxpayer-funded entity to one funded through tax dollars and new prescription drug user fees. Manufacturers pay these fees when submitting applications to the FDA for drug review and annual user fees based on the number of approved drugs they have on the market. However, it is a complex formula with waivers, refunds and exemptions based on the category of drugs being approved and the total number of drugs in the manufacturers portfolio."

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I do not see a straight line from how FDA is funded and its suboptimal procedures.

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Especially since you'd expect funding from pharma companies to lead to more approvals?

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I'll just say again, I do not see how reformed procedures would be much affected by the level or source of FDA funding. HCT would be less expensive, for example although yes larger trials to test various dosing strategies would, somewhat. And what did the funding have to do with the agency's reluctance to approve quick and dirty screening tests?

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The booster decision was interesting in this respect. If Biden had his way, boosters would have been rolled out for all in mid-September.

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The EUA legislation vests the power in the HHS Secretary (https://www.law.cornell.edu/uscode/text/21/360bbb-3).. HHS policy from a few years ago delegates it to the FDA Commissioner who has delegated it to the heads of CDER / CBER. So it's delegated currently to lifelong FDA bureaucrats who have been selected for and conditioned to have the exact wrong mindset that we need to save lives here.

Last year, around August there was a media backlash after it was revealed the Trump admin was putting pressure on HHS to EUA Pfizer's vaccine in early Nov before the election, an action which back-of-the-envelope calculations suggest would have saved ~10,000 lives.

Whether the president alone can do an EUA on their own is a bit murky (from what I've read probably not? or if they did there would be huge legal challenges). However the president could definitely fire the current HHS secretary and put someone in who would do an EUA.

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Governance of arms-length bodies is an interesting concept.

Counterpoint: Parliament allowed the UK government to relax the normal procurement rules to deal with the crisis and it's argued that they used this power to award contracts corruptly.

https://www.bbc.co.uk/news/56174954

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In your PPPS, you're comparing the reward of saving COVID deaths, vs the risk of you looking like an idiot.

This is extremely inaccurate, the real fear is: the reward of saving COVID deaths, vs the risk of cancer deaths / a higher rate of miscarriages / heart disease / whatever else can go wrong.

The latter aren't things you can say "I accept this risk" about... until you're appointed as Tsar :)

Waiting may mean more people die of COVID-19, but that is happening anyway. It also means that they have a greater chance of catching any horrible unintended side-effects that only manifest over time, which may not only counterbalance COVID deaths saved, but might turn more people against "the medical system" in general, leading to higher mortality.

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If rare side effects are the worry, they should have continued the trial and let it expand to 3,000 people. I can't think of any conceivable rationale for ending the trial but delaying approval.

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I agree with this! The trial should have continued, and in hindsight Pfizer was stupid for stopping it (unless it was forced on them by the FDA).

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What's the difference with giving the drug to the control group in this study, verse when they did the same with their vaccine (at the 3 month point in time into a six month study)?

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No. The trial cannot continue just because there is SOME small chance of rare side effect. There must be equipoise. Trial participants are not LITERALLY guinea pigs

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People in the control group are no worse off than the rest of the population who also doesn't get the drug.

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Ethics boards have made some odd decisions.

The idea that it is unethical to continue a trial once the preliminary results are in if those results show a large enough benefit means that it is more or less impossible to find even somewhat rare side effects until after the drug has been on the market for some time.

The people who are then affected are necessarily not in the trial, i.e. they didn't sign up to be experimented on.

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Assuming the drug is actually that effective in preventing deaths/hospitilizations from a disease that is currently causing huge amounts of deaths and hospitalizations, while in the trial of over 1k but less than 3k people found no serious/obvious side effects... even assuming it's as carcinogenic as smoking cigarettes for a decade, it would be worth giving to anyone presenting covid symptoms.

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Like I have a hard time exagerrating how good the initial trial results were. Its more like being shot and and offered a choice of standing in the open vs. hiding in a concrete bunker with no windows, but there might be some poisonous insects you can't see lurking in the corner.

Nothing is without risk, but some risks are stupider than others

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I'm not sure that the decision point for discontinuing the trial and the decision point for approving the drug should necessarily be the same thing.

Trials test for both efficacy and safety. There might well be a point at which you can say "OK, we have enough signal to know there's efficacy, but we need to observe all the already-dosed patients for another two months to check if any side effects pop up".

(This isn't necessarily what's going on here, I'm sure there's an element of bureaucratic inertia too, and of "Doing things the right way is more important than doing them quickly")

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Depends on the situation. In the setting of a global pandemic no they shouldn't be the same, the threshold for approval should be far LOWER than the threshold for stopping

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In general, they should approve when safety is ensured. Efficacy should be for prescribing doctors to decide based on available evidence (eg trials and papers).

That's how the FDA used to be run until a few decades ago.

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The reason to end the trial is that you want to give paxlovid to all the people in the placebo arm of the trial.

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I mean I get and support that, the point is that if sufficient data has been collected that we can effectively end the trial by giving paxlovid to the placebo wing, we should also approve the drug.

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That could be true in cases where a drug is given at any stage of a slow-developing disease, but I don't see how that's the situation here.

Per the linked Pfizer press release, the trial looked at Paxlovid within either 3 or 5 days of symptom onset. I can't imagine that the study is giving Paxlovid to any meaningful number of people in the placebo arm.

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If you think the side effects will show up in the 1200 already administered within the next few months.

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In which case the correct course of action would be to continue the trial until it's pre-registered endpoint, not stop it early, would it not? That the system allows both the termination of the trial AND the wait until approval is the point, I thought.

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Drug trials are expensive, why continue if you've already got enough data?

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No. Equipoise

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The pre-registered endpoint is something like "3000 patients, *or* sufficient evidence before 3000 patients to trigger an early stop". The early stop conditions are always pre-registered, and always factored into the p value, whether or not they are triggered.

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I think you are misreading him. He says he wants to maximize "expected lives saved", which accounts for any probability-weighted lives lost to side effects. He likely also intends to include lives lost to potential distrust of the medical system, in the unlikely scenario where something goes wrong.

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I agree that was the intention, but we don't know how many probability-weighted lives will be lost to side effects.

The reading of the sentence "If it turns out Paxlovid is terrible, yeah, I’ll look like an idiot - but I care about maximizing expected lives saved more than I care about my reputation." seems to indicate that any expected side-effects will be negligible and the largest risk is to Scott's reputation, whereas the FDA and cautious people (and conspiracy loons) likely rank the risk to Scott's reputation fairly lowly vs. risk of major side-effects.

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I think the confusion is from the word "expected", which is borrowed from the confusingly-named concept of "expected value" in statistics. The connotation for that term is that you weigh all the pros and cons probabilistically. So by using the term, Scott did not mean to connote the costs were negligible.

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I guess his statement does imply that the probabilistic costs of side effects are small relative to the benefits, and I agree.

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"We don't know how many lives will be lost to side effects" is true. A frequentist might say "We don't know how many probability-weighted lives will be lost to side effects," but that is nonsense in a context of Bayesian probability.

If you're confused about whether Yvain is a Bayesian or a frequentist, https://substack.com/profile/12009663-scott-alexander paraphrases Hillel as follows:

Astral Codex Ten

P(A|B) = [P(A)*P(B|A)]/P(B), all the rest is commentary.

Now, go and study.

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If there is a low probability of major side effects, but a high probability of saving your life from COVID, that multiplies out to a net benefit for making Paxlovid legal

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author

Sorry, maybe I was unclear there. I meant that I believe the risk vs. benefit of near certainty of preventing many COVID deaths, vs. small risk of a few cancer deaths, on balance says approve this now.

In addition to that social calculation, there's the *personal* calculation of "nobody ever got fired for going through the usual procedures, but if I say this should be sped up and it's wrong, I will lose lots of reputation".

I'm claiming that I'm doing the right thing by making the socially correct decision regardless of what the personally correct decision is, and asking the FDA to do the same.

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Looking at it further, maybe it was the framing of "X vs Y", where X = expected value, and Y = minor unrelated outcome?

I'm trying to think of a different phrase that would convey the intended message without noise 🤔

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But Scott is not the one deciding if the drug should go into use - he is deciding whether or not to make the post. His personal tradeoff is "should I promote this, even if later it may turn out I was wrong and lives are lost and my reputation is lost due to that" - as the post itself is unlikely to cause the drug to get approved or used much more, just that it gains awareness among his readers.

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I am not yet convinced of your "near certainty of preventing many COVID deaths" statement. This is only true if production is already so ramped up that there will be no post-release supply shortage or if fewer pills will be produced due to the delay.

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No. It’s the people not getting the drug between now and approval who will die in the meantime.

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They would. However, if the argument is to minimize expected deaths you need to account for the whole lifecycle. Under a limited initial supply hypothetical, you could approve now use all available pills. Some lives would be saved now and some people would die later because supply would outstrip demand. Alternatively, you could approve later. In which case more people would die now and fewer later because the pills you didn't give people earlier would be available to meet the excess demand.

Whatever you choose, the expected number of deaths is roughly the same. You can't work out the benefit without accounting for the production/demand dynamics.

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Yeah. Unless the drug has a very short lifespan, it probably doesn't matter if it gets approved now or in two months, as there won't be enough to go around and essentially 100% of the medication will be used either way. So it is really less "will save net lives" and more "it might save more lives now and less later" or vice-versa.

It's unlikely that waiting for approval will actually cost net lives.

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Earlier approval probably leads to faster supply chain scale up. The behavior of vaccine supplies suggests that a month or two faster approval would move forward availability for everyone by a few weeks.

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Merck has been producing their drug for a while now, and they aren't approved. Reality is that they are scaling up to produce the drugs because they fully expect to be approved, and they know they're going to be short even with that lead-up.

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The longer you push back the "we aren't giving it out" phase (for whichever reason, lack of approval or running out of drug) the higher the chance that that phase occurs after the pandemic is over.

Instant approval therefore still has +EV, the magnitude of which depends on how likely you think we are to run out and how soon the pandemic ends

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Don't worry, the pandemic isn't going to end anytime soon.

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A short term exposure to a chemical is not going to raise cancer risk noticebly. There are so many more chronic exposures to more mutagenic chemicals. We've also got tox studies in animals bred to be very sensitive to mutagens that rule out that sort of thing long before first in human studies.

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Probably not, but there definitely are chemicals that do raise cancer risk noticeably with short-term exposure, and not all of them are mutagens.

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Like what?

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I was thinking of asbestos, but there are probably other examples.

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I thought asbestos was pretty safe unless you smoke, and that the hysteria over it was irrational. Even if you smoked, would a short exposure lead to a noticeable increase in cancer?

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asbestos is mostly only dangerous to people who work(ed) in manufacture or installation of asbestos construction materials, because its harm is by physical damage to the lungs when you breath the tiny, razor sharp particles. I.e. if you live in a house full of asbestos insulation, your exposure will be minimal, because it's all inside of walls and generally undisturbed. If you are installing those walls, tearing them down, or on the production line handling lots of raw asbestos, your exposure is significant (but pretty well mitigatable by proper engineering controls and PPE)

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All of that is consistent with my understanding of it as well.

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Many highly radioactive ones can kill with short exposure, but it is via radiation.

I am curious which nonradioactive ones can do this.

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carbon tetrachloride (used to be in fire extinguishers. now mostly reserved for giving lab animals cancer for researchers to try to cure)

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How much needs to be given to cause cancer, and for how long?

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Guess what? We’re not going to know if a given drug increases the risk of miscarriage in humans until after-market trials anyway because pregnant women are usually excluded from most drug trials. But that’s a different problem that Scott might want to write another post about someday.

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Were pregnant women excluded from the Paxlovid trial?

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Yup. From clinicaltrials.gov, exclusion criteria ... Females who are pregnant or breastfeeding

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Shit. Thanks.

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Pregnant women are considered "vulnerable" by HHS Common Rule (a view held by many bio"ethicists") and thus they are bared from a lot of trials even if there is no rational scientific justification for it. Which is very discriminatory and anti-woman!

Some people are trying to change the system because it's so unjust and has led to vaccine hesitancy among pregnant women during the pandemic

https://www.politico.com/news/2021/11/01/covid-vaccine-studies-pregnant-people-518215

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Don't push too far in the other direction. The outcome is going full Australia and having vulnerable people (with anaphylactic reactions etc), who we are told are one of the reasons to push vaccinations as high as possible, being denied mandate exceptions.

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The drug should be offered, with the unknowns and untested parts made clear. It should be up to patients and their doctors, not the FDA, to then decide whether or not to take that risk.

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Ofcourse, there are unknown unknowns too.

Just say that as well.

It could save those 50000 patients.

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Given that ~90% of those deaths will be unvaxxed, 45,000 have already made their choice not to be saved.

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5000 is very high! Even 1 shouldn't die because the FDA is too concerned about its image and too eager to tell us what risk to take.

Tangent : The other 45000 : Come on, ppl make mistakes. They deserve to live too.

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Hersey! Once you disagree with the majority your life is forfeit. That's the only fair way!

/s

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uh, what's your point? Are you implying it's ethically permissible to withhold a life-saving drug from someone because they were too stupid to get vaccinated?

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It was a response to "It could save those 50000 patients.", pointing out that there's already a drug that would save 45,000 of those patients, so on what basis do you postulate that those 45,000 would accept a second drug?

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When the 45,000 refused vaccination, they didn't have COVID. If they're being offered Paxlovid, that means they do have COVID. Having vs not having COVID seems like a pretty good basis on which to change your mind about accepting COVID-related medicine.

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Doesn't cancer typically take years or decades to show up? What percentage of phase III trials actually last long enough to detect changes in cancer risk?

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But the individual that gets covid and wants to take Paxlovid can say "I accept this risk". The FDA literally is making it illegal for folks to make their own risk reward decision.

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Exactly. The FDA has no moral right to do that. These decisions ought to be between patient and their doctor only.

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In much the same way vaccine mandates make it illegal for individuals to make their own risk/reward decisions...

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Not the same way. Because taking the vaccine reduces the risk of your spreading the virus and of taking up a hospital bed with a severe case. It thus affects others.

We need herd immunity. Same reason other vaccines are mandated to attend public school.

I agree though that with a new virus, the details change slightly as new data comes in.

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The vaccine is not 100% protective against infection, nor does it reduce transmission 100% (Both numbers appear to be in the 50%-80% range depending on the vaccine). This at minimum weakens the case for a mandate. As far as taking up hospital beds? You might as well make carelessly breaking your arm illegal. Consider that, in America at least, people are *paying* for their hospital beds, through insurance copays or out of pocket. They have as much a right to a hospital bed as the next person.

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Watch this old video from Milton Friedman's "free to choose" lectures, on this very debate.

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If the vaccine were 100% protective against infection, then there would be basically zero case for a mandate, because people who care could just vaccinate themselves. If the vaccine were 0% protective against infection, then there would be zero case for a mandate, because the vaccine would do nothing to protect others. But when a vaccine is something like 80-90% protective against infection, there is an extremely strong case for a mandate, because the vaccine really does reduce the risk you pose to other people, and there is still a non-negligible risk that the other people are bearing from you even if they protect themselves.

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This assumes that the vaccines are sterilizing. They are not: https://www.npr.org/sections/coronavirus-live-updates/2021/07/30/1022867219/cdc-study-provincetown-delta-vaccinated-breakthrough-mask-guidance

The dropping efficacy and forever boosters makes it more of a sham.

Moreover, for kids, there is no actual proof that it they are effective at reducing severe outcomes since the clinical trial didn't have any severe cases in either arm... they used immunobridging to infer the "level of protection" by correlating it to antibody levels.

Even if they were effective at stopping spread or reducing severity, how is it at all ethical to force someone to take a medical procedure for someone else's benefit? If you are worried about COVID, you can get vaccinated and be protected. Yes, I understand some people can't get vaccinated due to health issues but I think that's a red herring. What percentage of the population is that?

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What do you mean by "sterilizing"? Do you mean 100% effective at preventing all spread?

It seems that yes, it absolutely is ethical to require people who voluntarily enter crowded public spaces to not do so unless they have undergone a medical procedure for the benefit of all the other people present there. With an 80% effective vaccine, each person's vaccination still leaves them some non-negligible concern, and thus makes it quite natural to ask that other people entering crowded spaces with them also do their part to reduce the risk by another 80%.

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That is at most an argument for taxes and subsidies. Not for outright mandates or bans.

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Fine, and then someone does develop cardiac problems in the long term, and then they/their family sue the doctor and the drug company and anyone else their lawyer thinks will stick over "you should have warned us!"

"We did, and you accepted the risk?"

"Well, you should have made sure this was perfectly safe!"

"But you didn't want to wait for the trials and approval process, you wanted it *now*"

"Well, you shouldn't have let us have it anyway, even if we wanted it and said we accepted the risk!"

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It's actually even worse than that. They are saying that *doctors* are too stupid to make the risk/reward decision for their patients. The drug will require a doctor's prescription. Doctors know the patients particular situation and have a lot of experience thinking in terms of risk/benefit trade-offs (unlike FDA stooges who use precautionary principle / are incentized just to minimize risk, and who have shown themselves to suck expected value thinking throughout the pandemic).

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Though off label prescriptions are still legal..

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Not for Paxlovid though, it's not approved by the FDA for anything, so it can't be prescribed off-label. [Ivermectin on the other hand can be.]

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If the FDA approves a wrong drug, there is a clear dead kid that the media can scream about, and the individual guy at the FDA who approved it can be dragged before Congress about why he likes to murder kids.

If the FDA fails to clear 100 drugs that each would save a million lives, there is no clear dead kid, because "I didn't get this medication and died" doesn't have as clear a line, even though we statistically know there must be millions of them.

I get why the FDA operates this way. But it's also a situation that can be fixed. We don't have to stay in this crappy situation forever.

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> you would think someone could either do a cost-benefit analysis (the risk of letting one terrorist through is less than the risk of having all these people get executed after Kabul fell) or take the initiative to come up with some clever solution (airlift them to a military base in the US, let them wait there, and don’t let them out until the not-a-terrorist background check clears).

For Vietnam, they called it Operation New Life and moved 50 thousand people to Guam in a month. I don't think I ever got a satisfactory answer as to why it wasn't possible to get started on something similar a decade ago.

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The US built the Arecibo Telescope in 01963, entered the Vietnam War in 01964, landed on the Moon in 01968, unilaterally "temporarily" reneged on redemptions of dollars in gold in 01971, made their last landing on the Moon in 01972, suspended combat activities in Vietnam in 01973, evacuated 130,000 refugees in Operation New Life in 01975, ended their manned spaceflight program in 02011 (although other countries still flew US astronauts, and in 02020 SpaceX resumed US manned spaceflight), allowed the Arecibo Telescope to collapse in 02020, and withdrew from Afghanistan in 02021.

In short, the US in 02021 is not the same as the US in 01975.

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What’s with the leading 0s there?

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Time traveller mistakes.

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Hmm. A good man to know them is Furrfu. Maybe he has a sports almanac lying around somewhere.

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The US developed a COVID vaccine in 10 months in 2020.

Maybe you should stop cherrypicking.

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Only one - moderna - was entirely a US developed vaccine as far as I can see.

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Some guys in Boston developed a covid vaccine in 4 days in 02020. Then it took them 10 months to be allowed to give it to people because of organizational dysfunction in the organization we're talking about: the US government.

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Yeh…it’s not like that had to test it to make sure it worked and was safe and scale up production. Nope they should have just instantly made up 600 million doses and hoped for the best.

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Human challenge trials could have sped that up dramatically. Under six months seems pretty plausible to me.

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If they had the right challenges. It's not obvious that the vaccines would have seemed effective depending on what kind of challenge they tried. It's also not obvious that a vaccine that is effective against the challenge they tried would be effective against the virus in ecologically real scenarios.

Challenge trials would have been very useful for determining the risk of various real-life exposures, and then what was learned from those might have somewhat sped up the vaccine trials. But I suspect that the real benefits would have been much more in terms of understanding which non-pharmaceutical interventions were valuable and which ones weren't, than in terms of speeding up the vaccine approval.

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We could have made up 10 doses and given them immediately to 10 informed volunteers. After a week, during which time the number of covid cases had increased 4x, if none of the volunteers died, we could have given 100 doses to 100 volunteers. After an additional week, during which time the number of covid cases had increased by an additional factor of 4, we would have known that the immediate lethality of the vaccine was lower than 2%, and we could have given 1000 doses to 1000 volunteers. Within another week, at which point the number of covid cases was about 50 times larger than when the vaccine was first developed and it had spread to most countries in the world, we would have known that the immediate lethality of the vaccine was lower than 0.2%, an order of magnitude better than covid itself, and we could have started giving it to thousands of healthcare workers in Wuhan. Within a few weeks we would have known that the workers who had received the vaccine were getting covid at a much lower rate than the workers who hadn't, so the vaccine was effective and much safer than getting covid.

This would have been late April, 02020. At that point the long-term safety of the vaccine would be unknown; if it caused leukemia three months later in 10% of patients, we wouldn't know yet. But we had excellent first-principles reasoning for believing that the long-term effects of the vaccine are a subset of the long-term effects of the virus itself. And we'd know that vaccine side effects at the two-month mark were mild. So the people of Wuhan would have been taking a risk if they all got vaccinated, but it probably would have been perceived a smaller sacrifice than the ones they were already making.

We could have stopped the pandemic then with the resources we had.

But because of the unearned arrogance and anti-rational strawman reasoning of people like you, as exhibited in your comment, we didn't. Tens of millions of people died, and we probably have a new worldwide endemic deadly disease.

Fuck you.

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"unearned arrogance"

"We could have stopped the pandemic then with the resources we had"

Guess the time travellers from the future still have a pretty good sense of humour.

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Not sure why this is a "win" for the argument that FDA is too slow... we are seeing now that efficacy drops like a rock and now it's boosters til forever.

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Efficacy doesn't seem to drop much for J&J/AZ.

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I saw one news story that said that, and another that said efficacy dropped from like 70% to 3% over 6 months for J&J?? Do you know what the reality is?

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It drops for all the vaccines that we have data on.

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What does this have to do with not approving it sooner?

"Not as beneficial as we hoped" is not at all the same as "had risks we had to dither on."

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"Not as beneficial as we hoped" == "Oops, the approved protocol is wrong, maybe we need three or four or N doses and we have no idea what the risks are there with this new protocol we're making up on the fly"

So now we are literally just winging it. What are the potential side effects? No idea, but according to a commentary article in Science (I think, don't have the citation handy sorry) about Israel rolling out boosters it had the throwaway line "88% of people reported side effects as mild as previous two doses." To me that reads: 12% of people had a worse reaction.

We are in uncharted territory now, worldwide, because we rushed the initial trials...

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Where is that "efficacy drops like a rock" thing coming from? As far as I can tell, the worst we've found is that 90% efficacy against infection has dropped to 60% efficacy against infection after 6-9 months, and 95% efficacy against hospitalization or death has maybe dropped a little bit?

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See https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3949410

"Method: A retrospective cohort study was conducted using Swedish nationwide registries. The cohort comprised 842,974 pairs (N=1,684,958), including individuals vaccinated with 2 doses of ChAdOx1 nCoV-19, mRNA-1273, or BNT162b2, and matched unvaccinated individuals. Cases of symptomatic infection and severe Covid-19 (hospitalization or 30-day mortality after confirmed infection) were collected from 12 January to 4 October 2021.

Findings: Vaccine effectiveness of BNT162b2 against infection waned progressively from 92% (95% CI, 92-93, P<0·001) at day 15-30 to 47% (95% CI, 39-55, P<0·001) at day 121-180, and from day 211 and onwards no effectiveness could be detected (23%; 95% CI, -2-41, P=0·07). ... [Similar story, different details for Moderna/AZ.]"

This is just one study, so who knows, it seems like every study comes up with a different decay rate. How abo0ut the UK's HSA COVID-19 vaccine surveillance report (Week 46? https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1034383/Vaccine-surveillance-report-week-46.pdf

Table 6 on page 23, first two columns, give rates of infection per 100k for vaxx and unvaxx. It shows for age ranges 30+ the efficacy is negative, reaching -100% for ages 40-49 and 50-59. The table shows that they remain effective against hospitalization and death. Taken together, this suggests vaccines are protective of the individual receiving them, but not "the community."

Yes yes, please read pages 14-16, the footnotes on page 24, and the blog post (https://ukhsa.blog.gov.uk/2021/11/02/transparency-and-data-ukhsas-vaccines-report/) and see if you believe their special pleading successfully hand waves away the literal doubling of case rates in the vaccinated population. Moreover, since the purpose of this report is to assess the vaccine performance *in the real world,* you really have to ask yourself if it's ethical to mandate a medical intervention based on this performance in the real world.

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People developed almost 100 different vaccines. That doesn't mean we have 100 functional vaccines.

You are engaging in selection bias. I could have come up with a "vaccine" against COVID in a week, but that wouldn't necessarily mean it would work.

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Manned spaceflight, especially to the moon, was always a vanity thing anyway.

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Most of the Americans left in Afghanistan were people who *wanted* to stay.

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Good post. A historical parallel is the AZT trial for AIDS. In that case, after halting the trial early because of clear signs of treatment success, the FDA gave Compassionate Use exemptions to 4000+ AIDS patients. Let me quote from a summary post of mine (https://willyreads.substack.com/p/a-history-of-the-fda):

"Phase 2 trials which had begun in February 1986 were halted early in September 1986 due to clear signs of treatment success, and AZT was officially submitted to the FDA for approval in December 1986. Eileen Cooper, a rising young star at the FDA, was in charge of reviewing it, and had been reviewing the AZT data for months before the official submission date. Even before the most militant AIDS activists had begun pressuring the FDA, she had been discussing with others on ways to speed and streamline the approval process.

She took two important steps. First, in September 1986 she had released AZT for compassionate use to 4000+ AIDS patients, which likely saved many lives. Second, she sought the support of the FDA's Advisory Committee on Infective Drug Products in a January 1987 meeting, which would symbolically back up the FDA's decision to approve AZT on the basis of a single prematurely ended clinical trial. This would achieve two contradictory goals: the rapid release of a likely effective drug to suffering patients; and satisfy the consumer protection and public health voices that generally urged caution."

So the FDA could and should have issued compassionate use exemptions for this drug, even going off historical precedent, while approval and paperwork checking was going on, as soon as the trial was halted for signs of treatment success.

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founding

You answered my question below. Thanks!

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Ivermectin is not the best choice for that question. We should ask why is fluvoxamine not being given to every high risk patient? There you have efficacy data just as good as for Paxlovid, and a far better safety record.

And there are around 20 other treatments where this question applies.

The six weeks of extra deaths until Paxlovid approval is basically what's been going on since the pandemic started. Almost all pandemic deaths are due to the failure to deploy probably-effective-definitely-safe treatments.

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author

Agreed on fluvoxamine.

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If someone you knew got Covid, would you write them an off-label script for fluvoxamine?

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author

Yes.

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Having first made sure the person was not allergic to fluvoxamine, on medications that would interact adversely with it, or having an existing condition or co-morbidity that would be worsened, such as cardiac disease or a history of same in the family.

There are several medications I can't take, because my doctor went "Let's put you on - oh, no, not with that condition of yours" or "let's try this new one, now there is the very remote chance of this side-effect but it's very rare", and after I took the first couple of doses I started getting the potentially very serious side-effect and had to discontinue sharpish, or else.

For example, with fluvoxamine, there is the risk of QT prolongation which affects the heart rhythm, in sufficiently severe cases causing something lovely called torsade de pointes, "a specific type of abnormal heart rhythm that can lead to sudden cardiac death":

https://en.wikipedia.org/wiki/Torsades_de_pointes

I know I'm susceptible to this, because I already have heart arrhythmia, and developed long QT interval after taking a common anti-histamine (fortunately for me, the cure there was "stop taking that and after a couple of days it will sort itself out").

So, no fluvoxamine for me, even if it works well for high-risk patients (and I'm the type who *is* a high-risk patient if I *do* get Covid).

This is what drives me crazy about such demands for "Give everyone X!" because this is the kind of "read the small print" need that people calling for X don't take into account.

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No need to be driven crazy. That's medicine. I'm sure we'll discover plenty of problems with Paxlovid. All I said is that we have a better safety record for Fluvoxamine.

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I don't think there is the same level of evidence for fluvoxamine as for paxlovid.

Paxlovid was developed specifically for SARS-CoV2 with (I think) a reasonably well understood mechanism of action. Their phase 2/3 study shows an effect on mortality as well as on the composite endpoint of hospitalisation or mortality.

Fluvoxamine is repurposed; no clear mechanism of action; was trialled initially for a pretty random reason (some person thought why not https://online.flippingbook.com/view/329200553/9/). The main study shows an effect on a composite endpoint of "observation in A&E for 6 hours"/hospitalisation/death. Almost all the effect is on the least objective component of this composite endpoint, the observation for 6 hours in A&E. There is a good reason to think that participants, and possibly treating physicians were not completely blinded to allocations given the very large differences in adherence between the SSRI and placebo arms. So I would worry the effect is being driven mostly by behaviour.

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There was a trending effect for deaths. While not statistically significant, it was the same relative risk ratio as for hospitalizations (0.68), which argues against the hospitalization reduction being driven by unblinded subjective factors.

https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00448-4/fulltext

> "There were 17 deaths in the fluvoxamine group and 25 deaths in the placebo group in the primary intention-to-treat analysis (odds ratio [OR] 0·68, 95% CI: 0·36–1·27)"

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I'm not saying there is no evidence for benefit, all I'm saying is from a Bayesian perspective the probability that SSRIs actually are useful is less (lower a priori probability, higher likelihood that the results can be explained by chance+bias)

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SSRIs as a class show no effect on Covid outcomes (https://www.medrxiv.org/content/10.1101/2021.10.25.21265218v1.full.pdf). The beneficial effects are specific to fluvoxamine, and they aren't that great if you consider death to be an important outcome.

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Observational data from hospital records could be horribly confounded in all sorts of way and in either direction. "adjusted logistic regression model was run to account for age category, gender, and race" doesn't cut the mustard I'm afraid...

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Isn't the "per protocol" group pretty impressive? (1 death in the treatment, 12 in control). Is that a usual thing, to separately track a subset of patients who reported high adherence to the prescribed dosage?

Naively it looks like a neat trick to me, if many patients aren't really taking the medication enough (because it's not administered in a controlled environment) then we're not really testing its effects and we should expect middling results, so let's focus on the patients who actually took the damn pills? I guess this biases for conscientiousness, but is that a cause for concern? I haven't really seen this "per protocol" thing before, genuinely curious what to think of it.

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Isn't this the missing story here? Good to see lots of action on Paxlovid and related efforts, but where's the show on fluvoxamine? That stuff was already looking good a full year ago (https://jamanetwork.com/journals/jama/fullarticle/2773108).

Why was its study not properly funded during the year? Don't governments have money to throw at a seriously promising treatment?

Then last month the TOGETHER trial came out with clearly positive results, positive enough that it was stopped early for fricken *efficacy*.... and what do we hear? Crickets! Where are the FDA and the EMA? Where are their equivalents in Third World countries that would have the most to gain from it?

I honestly don't understand.

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And meanwhile the monkey show goes on and on with Ivermectin, long enough to get Scott writing one of his longest posts ever! At least we got the fluke pun for it...

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Go read the TOGETHER study again. Specifically, Table 3, line 8. No effect on death rates. Even the primary endpoint, hospitalization, was less than a factor of two - and you still die. Time to move on.

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The Moderna vaccine was developed in March 02020, a few days after the genome was published. China was offering a covid vaccine to government officials and students who had to travel abroad in July 02020, a more traditional vaccine, I think. The Moderna vaccine was approved in the US in November 02020.

Not just almost all pandemic deaths but almost the entire pandemic are due to the failure to deploy possibly-effective-probably-safe treatments.

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Yep, the Chinese vaccine is a bog-standard killed-virus vaccine. It turns out it's about as effective as the flu shot against Covid Classic: not that great, but a lot better than nothing.

The big advantage of a killed-virus vaccine is that it's standard and easy to produce. MRNA vaccines use brand new machines which are super hard to make and use. Even if Moderna and Pfizer had been rubber-stamp-approved in March 2020, we wouldn't have been able to produce much of them for a long while. As it was, Pfizer was struggling to produce enough of its vaccine for the clinical trials. Maybe they would've gotten more if they'd actually been rubber-stamped in March and scaled up right then as fast as possible... but I wouldn't assume at all.

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Aren't the "brand new machines which are super hard to make and use" just thermocyclers? I guess I don't actually know how the mRNA vaccines are made. Aren't they just RNA? Whose quantity you can double with PCR once a minute? I'd think the problems you'd have with that would be more a question of purity, contamination, and mutation load, rather than production capacity. But what do I know? I've never so much as plated a bacterial culture.

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It's the microfluidic machines that stick the RNA inside lipid nanoparticles that's the bottleneck. This is needed to protect the mRNA from the RNAses we produce to make life harder for viruses. From what I've heard, they haven't managed to scale it up to industrial-scale equipment and are stuck running a bunch of bench-scale processes in parallel.

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Thanks!

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> The big advantage of a killed-virus vaccine is that it's standard and easy to produce.

Are you saying we could have had a standard vaccine in large volumes much sooner than we got with the mRNA rollout?

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Yes. Absolutely. It wouldn't have been so good, but it would've been a lot better than nothing. It would've spoiled antibody tests to see if people have ever had COVID in the past (people who've gotten Sinovac return positive on antibody tests; people who've gotten mRNA/J&J return negative because they've only encountered the one spike protein), but that's much less important.

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So I'm really confused now, because I had thought that the main benefit of the mRNA vaccines is that they could be formulated much faster than traditional vaccines.

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I think they can be REformulated faster in response to variant changes.

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Yes, once you have the production capacity. In March 2020, we didn't have the production capacity, so mRNA took a while.

Now, the problem is that the FDA has forbidden any changes without prohibitive tests. Pfizer had a Delta-specific vaccine back in July, but the FDA blocked it.

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I'm pretty sure that this is backwards. It's definitely standard and easy to produce a killed-virus vaccine, but it's not faster. It takes nearly a year to produce enough doses of the flu vaccine for people in the Northern Hemisphere, at the relatively low uptake rate that it usually gets, even though we've been investing in capacity for decades. Whereas the mRNA vaccines are being produced in larger quantities already, despite using new factories.

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Evan above seems to disagree, so I'm still not clear on the real answer. What is the main production bottleneck for traditional vaccines?

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I probably am stating this more confidently than I should be. I'd be interested to hear what Evan says.

This brochure seems to suggest that growing the vaccine in eggs isn't actually as slow as I thought, but there's a lot of processing that has to happen after that. And it also sounds like the entire process is run once in a given year, with the number of eggs involved selected for the projected demand, rather than running continuously. I don't know if there's something about one method rather than the other that makes continuous manufacture harder or easier.

https://www.gskvaccination.com/content/dam/assets/516007R1_FluVaccineManufacturingProcess.pdf

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founding

In the 1957 influenza pandemic, we went from "this strain looks like it might be scarier than usual" to large-scale vaccination in the US and UK in six months. Not at the numerical scale of 2020 Covid vaccine production, but I don't see why the process couldn't be parallelized on whatever scale is desired.

The mRNA vaccines are faster in that you can get your *first* dose faster, like maybe Dr. McCoy in the third act fast, whereas killed-virus takes I think two or three months to produce anything useful and attenuated-virus longer than that. If you've also got a large-scale encapsulated-lipid production line standing idle, then maybe the whole process is faster.

But of course we didn't have that in early 2020. We also didn't have any confidence in what was then a very new and untested technology. It would have been prudent (though fortunately unnecessary) to have someone working on a classic known-mediocre vaccine as a backup to the various clever new technologies we bet everything on.

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There's actually a whole lot of other vaccine candidates that had been worked on other than the ones that got approved. We just don't hear about them much. I think some of them were abandoned in part due to the others coming out sooner or better than hoped. It looks like there was one French company and one Japanese company working on inactivated virus vaccines, in addition to five or six Chinese companies, a couple Indian ones, and others by the governments of Iran, Turkey, Kazakhstan, and maybe more.

https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html

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"There you have efficacy data just as good as for Paxlovid". The TOGETHER study (fluvoxamine) did find a 99.8% chance of superiority over placebo for their primary endpoint of hospitalization, but the degree of superiority was no better than a factor of two (CI95% [0.52- 0.88]). For the secondary endpoint of death, the death rates were indistinguishable (2% vs 3%, p=0.24). In the Paxlovid study, the treatment arm had no deaths while the placebo arm had 10 deaths (~500 people per arm). If you care about dying, I don't think fluvoxamine is nearly as good as Paxlovid. Indeed, fluvoxamine appears to be worthless.

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"Despite two doses of Comirnaty, I was forced to take a regimen of Paxlovid".

Seriously, the vaccine and the drug are great, but do they have to make it sound like we are living in a negative utopia?

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The largely unanimous and bipartisan mocking of the abject terribleness of the name "Comirnaty" has been one the bright points of this whole pandemic experience for me. Don't take this away from me.

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What's so funny about that name?

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It sounds like you're trying to say "Community" with a mouth full of walnuts.

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I see "co-morbidity" which isn't something I want.

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founding

If effectiveness and safety were the reasons the FDA stopped the trial, then it makes no sense not to approve it. It would be interesting to know other examples of stopping a trial of drugs for the same positive reasons and when those drugs were approved.

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The same thing happened with Merck's drug, Molnupivir.

The stoppage was mentioned in an October 1st press release:

"At the recommendation of an independent Data Monitoring Committee and in consultation with the U.S. Food and Drug Administration (FDA), recruitment into the study is being stopped early due to these positive results"

https://www.merck.com/news/merck-and-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-the-risk-of-hospitalization-or-death-by-approximately-50-percent-compared-to-placebo-for-patients-with-mild-or-moderat/

The EUA legislation gives the FDA a lot of authority - they could EUA right now if they wanted. However, they won't EUA until the committee meeting, which they have scheduled for Nov 30th. https://www.fda.gov/advisory-committees/advisory-committee-calendar/november-30-2021-antimicrobial-drugs-advisory-committee-meeting-announcement-11302021-11302021

So earliest EUA is Dec 1st, 9 weeks after the press release, and 7 weeks after Merck submitted their EUA application.

Pfizer submitted their application Nov 16th. So the median Metaculus prediction of Jan 1st is in line with the Merck example, sadly (I say sadly because the death rate has been pretty steady at ~1,200 per day and case rates are going up again).

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Will rushing even save a single life?

I'm skeptical. Unless the drug has an insanely short lifespan, there's a good chance there won't be enough to go around for months no matter what we do.

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I'm skeptical manufacturing is the bottleneck especially at a big company like Pfizer and give the statements from the company. See a couple tweets I did on this here:

https://twitter.com/moreisdifferent/status/1461689013627150353

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Those numbers are all assuming there are no issues with scaling up production.

And we are at 100k cases/day, ish. 180,000 pills by the end of the year is nowhere near what is needed. And would only represent an order of magnitude increase in production.

Merck has been producing pills assuming their drug would work and be approved; they didn't wait for approval to produce their pills, they started doing it months ago at risk (i.e. if the trials failed, they would have piles of useless pills).

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Note also that molnupiravir is not a new drug; it has been kicking around for several years. It was originally developed to fight influenza. So they've had more time to work with it - it entered phase I trials against influenza in 2019, before the pandemic even began. They've had a lot more time to work out the process for mass manufacturing.

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All good points.

Pfizer has requested that the initial EUA be considered for high-risk patients only so hopefully the FDA/CDC/doctors will all work to ensure the limited supply is targeted accordingly.

Please check out my post from this morning - it addresses some of the other objections that have come up in this comments section:

https://moreisdifferent.substack.com/p/the-fda-has-blood-on-their-hands

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By the way, I don't know _anything_ about biochemistry, but the new Merck RNA-garbling pill molnupiravir sounds a tiny bit ... terrifying. From StatNews:

Will it affect a patient’s DNA?

This is really a question only for Merck’s molnupiravir, since it works by sneaking subtly corrupted parts into the coronavirus’s RNA sequence.

Once the virus has mutated too much, it can’t work — mission accomplished. But there’s a theoretical chance that molnupiravir could also influence normal human DNA when it replicates, too. If mutations happen during that process, it could spell real trouble.

Merck did some tests during molnupiravir’s development to check this possibility out. In two different types of animal studies using higher and longer doses than are given to humans, Merck’s scientists didn’t see any increased risk of unwanted mutations. ...

But UNC’s Swanstrom isn’t completely convinced that the tests Merck did were sensitive enough. In August, he and his colleagues published a paper in the Journal of Infectious Diseases showing that a key metabolite of molnupiravir could mutate DNA in animal cells.

Given these results, Swanstrom said he would be particularly interested in seeing a long-term study of people who took molnupiravir to continue to monitor this potential effect over the next 10 or 20 years.

“This thing is going to go into thousands of people. And are we just going to ignore the fact that there’s this potential risk?” he said. “The risk could be zero. It could be no worse than going to get a dental X-ray — or it could do something more. But unless we find out, you know, we’re going to learn this lesson the hard way, way later than we should.”

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Merck's pill is said to be only 50% effective at keeping newly infected covid patients out of the hospital, compared to 85%-89% for Pfizer's new pill. So, if you can only take one, you'd want Pfizer's.

But, if they operate wholly independently, it would be nice to have Merck's pill available to double the efficacy of Pfizer's pill alone.

We need more tests to figure out if that is true.

We also need studies of how these pills work on the vaccinated. I believe the initial efficacy studies are only of the unvaccinated in order to get a sufficient sample size fast enough.

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It's a case of duelling experts once again.

Looking this up, there's an infectious diseases expert warning about use:

https://newsinfo.inquirer.net/1518775/be-careful-in-using-covid-drug-molnupiravir-infectious-disease-expert-warns

"Please be careful with molnupiravir. Long-term use has mutagenic potential. It is currently only for high risk populations with CONFIRMED mild/moderate COVID infection under compassionate use and only for 5 days. Beyond that narrow application, the risk-benefit ratio of this drug remains UNCERTAIN and can be potentially harmful. If you have severe COVID, it doesn't really work and other meds need to be used. NEVER take any meds without proper medical consultation. Stay safe!"

So maybe not quite the same thing as Paxlovid, and certainly it sounds as if caution in using it is warranted.

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And of course Merck's press release is going to downplay any concerns and claim that it's safe, wonderful, and should be on sale right now. I'm not calling them liars, I'm just saying that after pouring millions into developing this, they want to see a return on that as fast as possible.

There's also a political angle, so I don't know if this guy was being honest or just another anti-Trump official:

https://en.wikipedia.org/wiki/Molnupiravir

"Alleged safety concern

In May 2020, Rick Bright, director of the US Biomedical Advanced Research and Development Authority (BARDA), filed a whistleblower complaint, alleging that the Trump administration ignored his early warnings about the COVID-19 pandemic, pressured him to inappropriately fast-track unproven drugs, and illegally retaliated against him by removing him from his role as head of BARDA in April 2020.

Among these complaints, Bright objected to providing additional federal funding to Ridgeback Biotherapeutics to further develop molnupiravir into a treatment for COVID-19. He argued that although the drug had shown potential against coronaviruses including SARS-CoV-2, it had already received substantial government support."

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Much of the cost benefit analysis is predicated on Pfizer being able to unleash a flood of pills. If production takes time to ramp up and demand exceeds supply at any point during the initial post-approval period, then the cost (in lives) of the delay would be near zero.

I don't know, and have not been able to find any information on, what Pfizer's production curve looks like. I'd love any sources on that folks could share.

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It would be near zero. In theory they could auction of the pills to the most efficient user.

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Probably the most efficient user is not in a position to participate in an auction because they are intubated and heavily sedated.

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It must be given in the first 5 days of symptoms so you've missed your window if intubated. That said, your point still stands. The person in a position to spend the most at auction is likely not the one who it will be most likely to help.

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Oh, I didn't realize that. Thank you. In that case an auction would probably be fine.

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And my point wasn't so much that a literal auction would be the best way to go about things.

But in general, if a good is available earlier (and can be stored) that has (economic) advantages over later availability, even if the total amount is the same.

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Huh, An auction seems bad to me. Rich people will buy it and save it, instead of the drug going to infected people.

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If they've already got the factories churning under the assumption that approval will be granted, does it really matter in the long run? Like, those pills will be made tomorrow, they'll find patients to take them, they'll save lives. Whether they save lives in a week or in 2022 doesn't seem relevant from a policy perspective.

And if drug availability is the bottleneck, it makes sense from an optics perspective to build up enough of a stockpile to not have stories about rationing and bare shelves as soon as approval is granted.

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I believe Scott's argument is essentially: it matters to people who die in the interim.

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Yeah, but Scott cares about (average predicted) number of lives saved. If 10 people get saved tomorrow, but then three months down the line 10 people die due to supply issues, how is that any better than waiting for approval and saving the latter 10?

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The 10 people saved tomorrow had no good alternative treatment options while the 10 people 3 months down the line will have other options besides this one because (following the lead set by this one) other new treatments are likely to have been approved. And we'll know more about how well this one works - like we might work out (based on the early use) that half-doses work well and thereby double the supply.

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Very true, and those 10 people will have lived another 3 months!

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One word I don't see mentioned anywhere is "manufacturing." It's one thing to make enough drug for a clinical trial, it's another to make millions of commercial doses reliably. FDA approval requires inspection of and confidence in these commercial-scale manufacturing processes.

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I was thinking this too. Although manufacturing shouldn’t preclude approval.

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To expand on this more: the clinical trials only show that *that one particular batch* was safe and efficacious (the FDA thinks this, since they agreed to terminate the trial early). Pfizer must then show that the commercial batches will be identical in every relevant way to the clinical trial batches, so that they will have the same safety and efficacy. What are the relevant ways? Pfizer must decide that, and justify their decisions to the FDA with supporting evidence.

Scaling up chemical manufacturing is not trivial (a regular contender for Understatement of the Year). E.g. heating and stirring work differently in different sized reactors. Heat transfer in and out of your reactor works through surface area, but heat produced/consumed by the reaction depends on volume. If your stirrer design isn't right for the viscosity of the solution, you might get hotspots and so on.

Ideally, the FDA expects you to understand the chemistry so thoroughly that you know everything that can possibly go wrong, and design your commercial process so that none of these things can possibly happen. The commercial batches will therefore be identical *by design* to the clinical trial batches, and you have to prove this with science. Of course in practice you don't have to have collected all the evidence before you can start selling batches, but you must have your plan in place with a solid scientific justification for every decision you made along the way. It also helps to have made a statistically valid number of commercial batches to show that your beautiful process works as designed (how many batches is that? you tell me, and justify your decision).

Pfizer/Merck will have thrown everything at this problem alongside the clinical trials, as they can afford to do this, so their regulatory submissions will be pretty good. However they still might have to store the new batches for a few months to demonstrate that they have a comparable shelf-life to the old batches, and FDA might wait to see this data etc.

Note that this really only applies to new chemical entities; people have been manufacturing fluvoxamine for years and its probably well understood by now. Not always true though; we saw a worst-case situation recently with the ranitidine withdrawal: a medicine that some reasonably healthy people take every day of their lives was shown to be contaminated with small amounts of a nasty carcinogen. If Pfizer happened to have some gaps in their understanding for the Paxlovid process, the FDA might go easy on them as dying of Covid now is worse than a slightly increased risk of cancer in the future, but it takes time to review all of these risks and make a justified decision.

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Yeah, unless the medication has an insanely short shelf life, it's likely that they'll be short on it regardless for months anyway as they ramp up production, and having bad batches of pills could kill use of the drug even if it does work.

Same reason why we didn't just mass innoculate people with experimental vaccines last year - a lot wouldn't work, so it would undermine confidence in the ones that did.

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To also expand on this: There's a real-life example as well. The EMA (the European counterpart of the FDA) is still reviewing the Russian Sputnik vaccine, and says the current delays are due to their inspections of the manufacturing facilities. Some EU countries, e.g. Slovakia, did not wait for EMA approval, and bought Sputnik early on. Then they found that what they received wasn't really what they expected (a claim the Russians hotly disputed).

https://www.nytimes.com/2021/04/08/world/europe/slovakia-coronavirus-russia-vaccine-sputnik.html

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Thanks for this. I see the commentary from Scott and others about how "why doesn't the FDA just approve it already and save tons of lives", and all I can think is, "You should know better; it's a lot more complicated than that."

Scott makes a lot of assumptions he doesn't even realize he's making when he assumes it's as easy as just churning out a bunch of this stuff in record time. I manage the clinical portfolio for a startup oncology-related pharma company, and I'm amazed when I see the speed at which some of these companies are pushing COIVD-related drugs.

Every step in this process takes a lot more time than people realize, and there are a lot more steps than people realize. It's not just the regulations that makes this take time. It gives me a lot less confidence when I see Scott talking about something within my field of expertise and making wildly inaccurate assumptions, that when he's speaking about something outside my field of expertise he's not making the same wild assumptions.

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What are the assumptions, then? You are the expert. If you don't tell us, we won't know.

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Scott's thesis appears to be: Paxlovid efficacy has been demonstrated to be 90%, with no strong safety concerns; the FDA's delay in approving it until Q1 next year will cost tens of thousands of lives; if they approved it sooner that would save tens of thousands of lives.

But I don't expect them to roll out enough doses to save even a majority of those patients if the approval comes tomorrow. I'm sure FDA approval is in the critical path, but it's not the only thing keeping patients from getting the drug.

If we can blame the FDA on the people who die while they're in the midst of their admittedly expedited review of this drug, does that mean we also get to blame the person working in the manufacturing facility for not making more of it? Or the analysts confirming the CoA? How about the project manager who accidentally got key priorities mixed up? Are they responsible for thousands of deaths, too? Should the medical writer be ashamed of taking Thanksgiving off instead of turning around the FDA meeting request documentation a little early? What about the people working in regulatory, legal, biostats, etc.?

There are a lot more people behind the approval, manufacturing, and launch of any treatment than just the FDA. A pharmaceutical company knows when they have good data and are likely to get an approval. They know the government is already guaranteeing they'll buy doses. Say we 'fix' the FDA approval issue and get an approval a few weeks early. Who do we go after next? Who gets the death toll blamed on them for not doing their job fast enough?

I'm only asking because I have a dog in this fight. I work in cancer, I believe what I'm doing is important, and I believe my company's approach has the potential to change the way we treat the disease eventually. I and everyone I work with are working hard to accelerate the process, but I'm also taking a vacation this year to spend time with my family. If we're successful and we produce a few drugs that dramatically change the nature of cancer treatment, I just want to know when they'll come blaming us for not getting the work done sooner.

Sorry, I realize that comes across a little hostile. I'm just watching all this COVID-related research happen at lightning speed compared to 'normal' clinical development like what we're doing in oncology. And then the public reaction seems to be, "Sure, but why didn't you do it faster?"

Kind of like this: https://www.youtube.com/watch?v=PdFB7q89_3U

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And then after pouring all the money and effort into making an effective vaccine in record time, you still have 10%(?) of the population screaming about how they won't take it because the Bill Gates microchip will let the Jewish Space Lasers control my mind and fascism and freedom and my DNA is going to get all evil and stop calling me stupid and I want a hug and to own the libs. It can get you down, if you let it. I like the German Health Minister's take: "Probably, by the end of this winter, as is sometimes cynically said, pretty much everyone in Germany will be vaccinated, recovered or dead." It's a calming thought. (OK. I'm better now.)

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My admittedly not that well informed impression of this is that governmental regulatory agencies are uniquely bad at their job compared to everything else in this pipeline. I suspect this is due to misaligned incentives. The researches and project managers have an interest in making working medication, and having it be there fast. I have the impression that institutions like the FDA do not. Their sole incentive currently seems to be not having people suffer side effects from medication ever.

This seems like something that might be fixed if broader groups of people became conscious of the trade-offs involved with this epsilon risk tolerance approach. Then the FDA could be held accountable for the consequences of their policies, shifting their incentives. Hence, complaining loudly about the FDA seems like a possibly useful thing to do.

I do not see any similar systematic ways to improve the work of research labs and pharmaceutical companies. Their incentives seem about as well-aligned as we can make them, at least in this capacity. Hence, I have no reason to complain about them. If we wanted them to work better and quicker, the obvious solution would be to pay them more. I don't think that would work with the FDA or other FDA-esque organisations.

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All I can speak to is my own personal experience. The division of the FDA I've been working with does not fit the description you just gave. Indeed, we met with other PhD scientists who gave valid commentary and suggestions, people who had reviewed our submission thoroughly enough to comment on nuances we wanted to highlight/discuss.

I'm not saying the complaints you have aren't valid, I'm just saying I don't recognize the FDA you're describing from my interactions with them. We met with a group of people who were interested and engaged with the process, even if the interaction was not a normal collaborative discussion.

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It's also worth noting that the 90% efficacy rate is based on an absolutely tiny data set. I don't actually expect it to be 90% effective.

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Look up Gell-Mann amnesia. You seem to not have it.

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Is there a Gell-Mann paranoia? This past year I feel like I've contracted that, where I see sustained bad reporting in my field that I just assume it's all bunk and stop believing anyone about anything. In early 2020 I thought it was a great time to be an immunologist...

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Amen. Whenever I read about X my response is either "I'm not going care about X, so, whatever" or "OK, now I have to spend quality time on PubMed to see if what I'm reading has any points of contact with reality." The upside is that I've learned a boatload by reading all those papers.

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During the pandemic, I have learned that a lot of people can convince themselves of untrue hypotheses by going to the primary literature when they don't have a solid foundation in the subject matter. For example, biologist PhDs who don't know immunology convinced themselves that early reports demonstrated antibodies weren't long-lived for COVID-19 because they didn't understand normal effector B-cell contraction, and related concepts.

PubMed is certainly useful, but a quick search of the primary literature isn't a replacement for a PhD anymore than a quick search of WebMD is a replacement for an MD. Which is a little depressing when I want to go spend some quality time on PubMed confirming whether X is real or not.

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I mean, you should. Reporting is absolute garbage.

It's just as bad about everything.

Look at the Rittenhouse case, and how many articles are completely at odds with the reality of what happened.

They're the kind of errors that would be made by people who didn't even look at the videos.

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The people at the FDA have to read and analyze these applications which can run tens or even hundreds of thousands of pages. That takes time even if you have adequate resources, which the FDA does not. That’s how we avoid another thalidomide, which would be the worst possible outcome. They seem to have an all hands on deck approach here, but it does take time, and it is necessary to dot all the I’s and cross all the T’s.

Perhaps I am being too solicitous, but that’s my take on this situation.

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