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.
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.
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.
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...
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?
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.
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.
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.
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.
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.
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.
"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."
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?
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.
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.
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.
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.
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)?
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
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.
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.
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
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")
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
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.
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.
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.
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.
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.
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.
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.
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.
"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 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
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.
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.
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.
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.
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.
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.
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.
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
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.
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?
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)
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.
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
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.
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.
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?
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?
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.
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?
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.
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.
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.
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.
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?
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%.
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!"
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).
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.
> 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Your photos get 4/5 from me
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...
Imagine the studies that could be done!
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?
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.
> some nebulous notion of distrust
The lack of trust in institutions has been real and had real-world damage done to the country.
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.
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.
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.
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.
The main limitation on something like the capacity of the FDA is funding, and that's controlled by congress.
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.
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."
I do not see a straight line from how FDA is funded and its suboptimal procedures.
Especially since you'd expect funding from pharma companies to lead to more approvals?
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?
The booster decision was interesting in this respect. If Biden had his way, boosters would have been rolled out for all in mid-September.
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.
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
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.
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.
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).
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)?
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
People in the control group are no worse off than the rest of the population who also doesn't get the drug.
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.
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.
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
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")
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
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.
The reason to end the trial is that you want to give paxlovid to all the people in the placebo arm of the trial.
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.
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.
If you think the side effects will show up in the 1200 already administered within the next few months.
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.
Drug trials are expensive, why continue if you've already got enough data?
No. Equipoise
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.
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.
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.
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.
I guess his statement does imply that the probabilistic costs of side effects are small relative to the benefits, and I agree.
"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.
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
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.
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 🤔
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.
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.
No. It’s the people not getting the drug between now and approval who will die in the meantime.
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.
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.
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.
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.
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
Don't worry, the pandemic isn't going to end anytime soon.
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.
Probably not, but there definitely are chemicals that do raise cancer risk noticeably with short-term exposure, and not all of them are mutagens.
Like what?
I was thinking of asbestos, but there are probably other examples.
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?
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)
All of that is consistent with my understanding of it as well.
Many highly radioactive ones can kill with short exposure, but it is via radiation.
I am curious which nonradioactive ones can do this.
carbon tetrachloride (used to be in fire extinguishers. now mostly reserved for giving lab animals cancer for researchers to try to cure)
How much needs to be given to cause cancer, and for how long?
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.
Were pregnant women excluded from the Paxlovid trial?
Yup. From clinicaltrials.gov, exclusion criteria ... Females who are pregnant or breastfeeding
Shit. Thanks.
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
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.
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.
Ofcourse, there are unknown unknowns too.
Just say that as well.
It could save those 50000 patients.
Given that ~90% of those deaths will be unvaxxed, 45,000 have already made their choice not to be saved.
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.
Hersey! Once you disagree with the majority your life is forfeit. That's the only fair way!
/s
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?
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?
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.
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?
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.
Exactly. The FDA has no moral right to do that. These decisions ought to be between patient and their doctor only.
In much the same way vaccine mandates make it illegal for individuals to make their own risk/reward decisions...
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.
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.
Watch this old video from Milton Friedman's "free to choose" lectures, on this very debate.
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.
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?
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%.
That is at most an argument for taxes and subsidies. Not for outright mandates or bans.
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!"
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).
Though off label prescriptions are still legal..
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.]
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.
> 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.
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.
What’s with the leading 0s there?
Maybe it's a Long Now thing? https://en.wikipedia.org/wiki/Long_Now_Foundation
Time traveller mistakes.
Hmm. A good man to know them is Furrfu. Maybe he has a sports almanac lying around somewhere.
The US developed a COVID vaccine in 10 months in 2020.
Maybe you should stop cherrypicking.
Only one - moderna - was entirely a US developed vaccine as far as I can see.
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.
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.
Human challenge trials could have sped that up dramatically. Under six months seems pretty plausible to me.
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.
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.
"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.
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.