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.
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.
> 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.
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.
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.
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.
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.
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.
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.
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.
It seems to me the same people who complain that they are being idiots for not doing something are the same folks who will complain when they do something and it blows up in their face. Tons of 20/20 hindsight, etc.
> I came away from the pushback convinced that nobody would ever believe the FDA was dragging its feet until I could make them read about it in flagro delicti - write a post saying the FDA is dragging its feet now, on this thing that you and I currently realize is obviously good.
Out of curiosity, does "stop the trial" mean "stop collecting data and give the drug to everyone in the control group" or does it mean "stop collecting data and stop giving the drug to anyone".
if it means the latter, then I fail to see how "it would be unethical to continue not giving to to the control group" makes sense, given that the potential control isn't getting it either way.
I'm uneasy with the elimination of a control groups by ending a trial early and giving the drug to the control group. They did this with the vaccine, too. Okay, it's hard to say no to the obvious humanitarian argument. Still, at the point when the control group is eliminated, all we've learned is that the drug seems safe and effective (for some p-value) in the short-term; we don't know anything about the long-term.
"Like everyone else, I hate the fact that pharmaceutical companies are the only people with enough resources to run high-quality studies, and that this controls what drugs we end up using."
For COVID the single most influential clinical trial in terms of drugs we are (and are not) using is RECOVERY - not a pharma led trial
It seems entirely reasonable to wonder why it ever had to be 'amateur hour' with ivermectin testing. Well, 'wonder' is not stating it genuinely. It seems entirely reasonable to observe that there was an obvious motive not to trial ivermectin with the same zeal as Paxlovid.
> I know I’m not going to convince many ivermectin supporters. So consider this: ivermectin is FDA approved. It’s approved against parasitic worms, but that’s fine: once a drug is approved for anything, any doctor can (more or less) use it for whatever they want. Doctors can absolutely prescribe ivermectin right now if they want, and many of them (like Pierre Kory) have. The ones who don’t prescribe it are avoiding it because they think it doesn’t work, not because the FDA is trying to prevent them.
False. You seem to be a bit removed from the situations hundreds if not thousands of patients have faced. Doctors even. Doctors getting placed on leave, fired, discouraged from prescribing Ivermectin. Even Pharmacists are banding together on /r/pharmacy saying they won't fill the prescriptions. Heck, Dr. Paul Mark, Front line critical care doctor, suing Sentara hospital in Virginia because Board of Directors wouldn't let him prescribe it.
It could also be FDA is playing the long game. The cost of a false positive for a drug approval is enormous as it erodes trust. So maximizing saved lives on a long enough of a time horizon could actually be withholding a drug that's virtually certainly good.
It could also be that it's bureaucracy in its worst. I don't know why they can't sit around the clock and do whatever they would do in six weeks in one.
Forgive me if this is a silly question, the first time I'd heard anything about Pavloxid was today. Which leads me to my question: why isn't this ALL OVER the news? I guess I would understand the FDA stuff flying under the radar, but there's not even a single headline letting anybody know that "Wildly Effective Covid Drug Has Been Discovered And Is For Real This Time"? Is it because of the chloroquine stuff? Is it because the Kyle Rittenhouse verdict just came out? Is it a coincidence?
I asked some friends who are progressive leaning peers at my fancy schmancy small liberal arts college, and they also had never heard of it.
I'm not familiar with this particular decision but when I was involved with a study that stopped early it was the DSMB that made the ethical decision. Are you sure it was the FDA that stopped the trial? If not, there is no ethical paradox. I for one wouldn't want the FDA to cede regulatory/ethical decisions to a heterogeneous collection of study boards of mixed quality.
"I honestly believe they’re operating on Fast Mode, well aware that the entire country is watching them and yelling at them to move faster."
Government bureaucrat time is not like human time. If i ran the zoo, I would have soldiers surround the FDA during the middle of the day, and I would tell them: "Free pizza and Coca Cola, but no one leaves until you have this nailed down."
Soo...if this drug works this way - does anyone predict that they will roll back the vaxports and other casual removal of various rights for not getting vaccinated? Covid was never more than maybe 5 or 10 times more deadly than the flu. If this makes it 10 times less deadly then covid is just another version of the flu essentially. Will we have some two tiered society and somehow in 20 years you'll still be barred from certain jobs if you're not vaccinated against Covid?
In a country and world where tobacco and alcohol are legal and fast food is subsidised through things as varied as cash handouts to big ag, tax breaks or zero tax for companies, and profit friendly ultra low minimum wage levels below the poverty line... In a nation where we know that the people in charge really really care about us, but just can't bring themselves to ban tobacco when they are in the mood to start banning things and firing people 'for our protection'. Will they remove all the mandates and stop firing people for not getting a vaccine they don't need?
Or will vaxport authoritarian madness carry on and expand into a medical social credit system and you'll get fired for not getting a flu shot every year and covid boosters forever? Will you be banned from attending University? Will you be barred from jobs. Will you be disallowed from travelling internationally or across certain state borders? The new regime of restrictions will serve no covid relevant purpose and protect no one from anything, but that doesn't mean they would stop the McCarthyist era style blacklisting of people. Oh you didn't get your flu shot and it was due last week, sorry you can't come into our restaurant?
I'd be predicting that such measures will become entrenched and slowly expand like most other forms of power creep. No one had or needed passports 150 years ago, but now everyone has to use them.
On the other hand, the good news is Pfizer will never have a negative quarter ever again with those Booster profits coming in, even if they have a pay out a few billion more in lawsuits from their criminal behaviour which results in people dying. Things are looking up for the upper class who will be able to buy into some system to skip the queue for all that vaxport stuff just like they can skip all the patriot act airport restrictions through buying a VIP pass.
I'd put this at 80% confidence....with the failure mode for more centralised power expanding would be some early and rapid defeat in the courts while they try to roll out their authoritarian plans further and further. So almost 100% the government will try, but maybe 80% chance they'll succeed. It isn't like any meaningful number of the patriot act era rights removals were ever restored. Will China take over the US's global leadership role or will the US simply become China through a medical apartheid?
I believe that this latest trend in destroying the control/placebo group is terrible. While they argue that the net benefit to the (in this case 612 users) control group is too great to ethically continue, significantly more than 612 potential consumers wont trust the drug because of it.
I expect this will become the "status quo" in drug testing moving forward, and it will only be a matter of time until a major problem hurts a large population.
Speaking of predictions - anyone care to speculate what will happen once it is approved? Will anti-vaxers refuse to take it? Will its use get politicized? Will it end the pandemic so I can get my former happy life back?
A quick look at clinicaltrials.gov shows 11 studies, 7 still in progress, concerning PF-07321332/ritonavir. Some are designed to look specifically at plausible bad interactions with common drugs. It's nice if the efficacy trial with ~1000 patients doesn't show any random safety problems, but it would be malpractice to not complete the safety tests on plausible bad drug interactions before unleashing it into a population that's going to be using it together with 100's of other drugs. Would you approve a drug without even a small test on people with hepatic impairment?
Am I the first to notice that the name is too damn similar to the drug in the fiction series Firefly? The one with rather extreme effects not noticed unless after distribution? A rather poor name choice for something we want hastily approved.
The argument that it is silly to stop the trial and then drag your foot with approval is strong (but there is a good comment below about the scaled up production process etc.).
But more generally, it sounds a bit polemic to me to speculate that the FDA is concerned with its reputation. Maybe at stake is not the reputation of the FDA, but the reputation of the approval process? Assume the case a drug is approved "prematurely" and saves 30000 lives but completely unexpectedly kills 10000 patients (who would otherwise have survived). What sounds like a great net positive outcome might still be very negative on the long term: Many people might lose trust in approved medication or evidence bases medicine in general.
Also, I am a bit surprised that Scott seems to use "expected value" so freely in this context. Medical ethics does not seem to work that way at all? At least, there seems to be a heavy asymmetry between action and non-action, maybe that is reflected in the approval system as well?)
How much is it worth for someone within the FDA to send this article to whatever the largest internal distribution list they can find is? Assuming they don't care about lives and just about being compensated for reputational damage, wondering whether lives * p(anything more happening | internal annoying emails) > happy price. Not re: me, I'd just do it. :D
"I care about maximizing expected lives saved more than I care about my reputation. Can the FDA say the same?"
Goodness, of course not. You're a mortal, with a finite influence and finite time, and by and by you will be replaced no matter what and your reputation will be of interest only to historians, at best. The FDA is immortal, and their reputation colors everything their future self does indefinitely. And it is actually *way* more important that generations of future Americans trust the FDA than that even as many as 50,000 lives in the present are saved -- because there are way, way more than 50,000 future lives at stake.
I'm not taking a position on how fast the FDA should approve this drug, but I am saying I think that your statement is too facile by half, and fails to acknowledge the importance of maintaining institutional trust[1] in an area in which people by nature have strong feelings. That is, and very well should be, a major priority at the FDA.
-----------------------
[1] I mean, would you even be feeling like you had to write a long screed on ivermectin, or fend off vaccine folklore, if institutional trust *hadn't* been lately damaged? Expensive, is it not, that kind of damage?
As an ivermectin supporter I just want to signal support for paxlovid.
As a conspiracy theorist, I do suspect it's just a rebranding of ivermectin (new molecule, same mechanism of action), but in any case, it Works! Let's use it! This isn't a left right divide, this shouldn't be any sort of X/Y divide, everyone likes paxlovid! Yay paxlovid!
This is really an asinine post. Why doesn't a regulator that chooses between life and death move faster and break things? The answer is inherent in the question. Calm down and let them do their jobs. When you push harder and criticize them, aren't you begging them to screw up? And at that point, your tune will change to griping about how they make bad decisions. Being a two-bit critic on the internet seems a lot easier than actually having responsibilities over human lives.
Realistically speaking, it's probably irrelevant whether they approve it now or in two months unless the drug has a very short shelf life, as they won't have enough of the drug to go around for a while due to having to work at ramping up production of it. Even if it was approved right now, I'm not sure if it would even save net lives.
They're probably using that time to make sure manufacturing is up to snuff and maybe looking over the data a few more times to make sure they didn't overlook something stupid.
The reason why we didn't immediately start mass inoculating people with experimental vaccines in 2020 wasn't because it couldn't save lives, it was that it could potentially cause serious issues with diminished trust if some of the vaccines didn't work, which could disincline people from taking the real ones.
The biggest downside of rushing out a medication is that it doesn't work and it erodes trust in future medications that do work.
The best moral argument I can construct for treating the control group and the population at large differently is that the control group has accepted some degree of risk in enrolling in the trial. Therefore they have provided the identical informed consent as the trial participants that are not control, while the population at large has not, and perhaps in some understanding of the facts cannot. The control group would in this argument not be morally equivalent to the population and low probability, yet-to-be discovered hazards can ethically burden the control group but not the population, assuming of course the control group has served their end in providing adequate data for the evaluation process.
I suspect the answer has more to do with some implicit assumptions about a difference between causing harm (active and specific) and allowing harm to take place (passive and diffuse). But that’s speculation.
I find it curious that some guy in his basement can legally sell a virtually untested LSD analogue online for months or years before the authorities get around to blacklisting it, but a company like Pfizer needs to wait for months for their drug to get whitelisted before selling any. So maybe the solution is for Pfizer to sell Paxlovid as a "research chemical" for home laboratory use :P
Many people have made the convincing riposte to this post that as manufacturing capacity will be the limiting factor, it doesn't matter that much how long (within reason) the FDA takes to approve Paxlovid.
I don't think this is as convincing as it first appears - Paxlovid isn't like a vaccine where you pretty much want everybody treated asap. So a country like the UK orders 200 million doses and tries to get the jabs into arms just as quickly as punters and jabbers can be lined up.
The antiviral will be given to vulnerable people, after infection and after symptoms develop. Which explains why the UK has ordered only 200 thousand doses. You only need as many doses as people who are getting sick (+ a few 'just in case', to be on the safe side)
My point is that supply may well equal demand, in which case delaying approval goes back to being a really bad thing to do.
I see this as a big problem, that only big business has enough resources to fund good clinical trials, because like this only treatments that promise good profits get rood evaluations. If anyone has a cheap or easy treatment gets just to hear 'It's not proven to work/be save, so shut up when the professionals talk'. So it's no wonder the costs of our health systems raise so fast.
Perhaps it would be a great project for ACXG+/++ to fund independent research or trials of promising cheap and easy treatments that are therefore not interesting for commercial research.
Big takeaway is that Agencies do not design their procedures along cost-benefit lines, especially failing to consider the cost in time of the procedure.
I'm sure I'm not the first to convey this sentiment, but I'm a little confused by this post. We all already know that with any governance system there is a trade off between centralization of authority - let's call it "having an X (e.g. medical, financial, educational) Tsar", in keeping with SSC tradition - and having lots of checks and balances in a more distributed system, which I'll call democracy (yes, I know democracy entails other things as well, it's just an ad-hoc term).
The more Tsar you go, you can act more quickly, be flexible as a society and respond to extreme changes in your environment. The down side is, if the Tsars themselves are human, they are prone to errors, corruption, or any other lapses of judgement, and can fail miserably. The more democratic you go, the more stable you are, with less chance for catastrophes of that sort, but unreactive and sluggish on the down side.
Current western society is not in the optimal point in this trad-off, probably a little too democratic. The way this manifests in reality is that the FDA will take six weeks to approve a drug that everybody agrees is effective. Not a year, mind you, six weeks, which to me sounds like a completely reasonable time to push papers hastily for a federal entity. And that's ok, cause what we earn by sacrificing speed is the up-side of a more democratic process (more insurance against huge errors).
So basically the entire point of the post can be summarized to "I wish we could move more towards the optimum, here's an example that makes this point very clearly." Well, yeah, but designing regime schemes is really hard. If we have a better solution to this (like earlier posts about the FDA) than awesome, let's discuss the solutions themselves and see how viable and effective they might actually be. If we don't, there's not really much to say.
Either way I'm not sure another example deserves its own post, and should, imo, be presented in the right context. Maybe a list of facts demonstrating how the US is too democratic (in the sense defined above) and not Tsar enough. Or just the FDA. Preferably, if there's also a list of opposite examples such that in time, we can try and compare the two.
Would be nice if stopping trials for this reason resulted in an immediate EUA. You can retract later if new data conflicts, but at least it's legal to use in the meantime.
"Perhaps there’s not enough evidence for the FDA to be sure Paxlovid works yet? But then why did they agree to stop the trial that was gathering the evidence?"
Researchers run on one system of ethics while the FDA runs on another.
I'm reminded of some old episodes of M.A.S.H where the main characters who were treating some injured POW's complained about the government not being able to decide whether they wanted to blow up these young people or put them back together in light of paying to do both.
" it’s pretty weird that the FDA agrees Paxlovid is so great that it’s unethical to study it further because it would be unconscionable to design a study with a no-Paxlovid control group - but also, the FDA has not approved Paxlovid, it remains illegal, and nobody is allowed to use it."
Possibly because Pfizer may have been a little bit naughty (allegedly!) in releasing all the data on their own vaccine trials, so the FDA are being careful not to simply rubber-stamp something a pharma company tells them?
FWIW, my wife was prescribed Ivermectin by her doctor recently (for something unrelated to Covid or worms) and basically no pharmacies in our (large metropolitan) area would fill the prescription.
Problems with this approach: if followed, manufacturers could have an incentive to submit poorly designed studies and profit from the distribution until the application is rejected. This in turn will cannibalize the proper testing and development of effective treatments.
This piece also neglects that the monoclonal antibody treatment is available and people taking an ineffective medicine would be denied such treatment.
Finally, this piece misses a discussion of what goes into the approval process so one can identify which steps could be skipped and what the tradeoffs are.
"Heck, people can get ivermectin even without a prescription as long as they use the veterinary version."
—people have, and ended up in the hospital, due to the dosage being way different and marine also the inactive ingredients. If you're mentioning the vet version you should mention that
If they stopped the trial prematurely due to effectiveness, then it is 99% guaranteed that the FDA will approve the drug. The threshold is much lower than for vaccines because this drug will be given to people who are sick and at risk of severe disease.
The reason for the delay is most likely that it takes a lot of time for FDA to review all the paperwork. The approval process includes a lot of validation. It is not only the trial results but every step related to manufacturing and ending with labelling. The pharma company first need to develop the scaled-up manufacturing process, validate all assays to show that the manufactured drug is what it says it is, free from impurities and at correct active substance content. Document all these validations and then reviewed by the FDA who will probably request some corrections and changes. Unfortunately, it takes quite a lot of time.
I guess that the prediction market is mostly right and possibly insiders already know tentative date of approval anyway. Unless the pharma company had done this preparation work in advance (someone knows for sure), the market predicted date should be approximately correct.
52 NDA - new drug applications are being held up due to a back log in the FDA conducting inspections of the sponsors (owners of the drug in question) and of the manufacturing facilities (not always the same as the owner of the asset). many biopharma companies use outsourced manufacturing - in many cases for both production of clinical trial materials & commercial products).
also, your PPS comment is provably false. There have been numerous cases in which hospitals have blocked the administration of ivermectin for covid patients - most notably in the recent case involving Dr Pier Kory's colleague Dr Paul Marik. Marik's case is interesting because it is not just IVM but all early treatments being prohibited by his medical administrators.
Also, the 'horse dewormer' propaganda campaign against IVM waged by the FDA, mainstream media among others is certainly an odd happening notably while the NIH confirms that IVM is being researched in clinical studies about its effectiveness against covid. a review of clinicaltrials.gov or the NIH's website confirms these facts.
It does seem like there ought to be some sort of “we have no reason to think this doesn’t work, go ahead and use it at risk while we review the paperwork” pathway for active pandemics.
I mean, they are waiting weeks to just have the Zoom call to decide whether to give it an EUA. That’s insane.
From the outside, it does seem like reputation risk, as Scott mentions, is a big problem at the FDA. I can somewhat understand their point of view. If people lose trust in the FDA's actual decisions (beyond just the current groups of critics), rather than mostly critiquing their inactivity, I could see how they would believe that would be more damaging to their societal authority as a regulatory body. But more transparency is a better solution than dragging their feet and being opaque. I would propose they make faster decisions, even if they're sometimes wrong, and publish public post-mortems on decisions, good and bad, to show the public that they're paying attention to the process and seeking to improve it. I think FDA reform could give us faster action and a stronger reputation for the FDA, rather than trading those two off as the FDA seems to believe is the case.
"But then how come the prediction markets are already 90% sure what decision they’ll make?" -- this seems to say that the prediction markets think there's a 10% chance it won't be approved at all. 10% is a sizeable number, why are we all suddenly so dead certain that it needs to be treated as 0?
(My issue right now is that it seems like we would've observed short-term side effects already, and I'm not sure an extra month will let us observe any long-term ones -- but this might be a false dichotomy, I really don't trust my intuitions on this enough to start screaming STOP THE TRIALS ALREADY. The CFR for Covid is not humongous, so it doesn't take a hugely common side effect for it to have the potential of outnumbering the Covid death toll.)
"Molnupiravir is saving lives in the United Kingdom; the FDA is blocking it here.
"If clinical trial results are accurate, another antiviral pill (Paxlovid) reduces the risk of hospitalization and death among high-risk COVID patients by 89%. If other countries approve it first, patients will again lose precious time as the FDA denies them the right to access the drug on the strength of those approvals."
From prototype (trials) to ultra large scale production (a pill for billions of humans) typically it takes quite some time. The naive western imagination yet is that a clever engineer throws a blue print for any product over the fence to the factory - typically seen imagined as a cheap Chinese factory full of dumb human robots. Days or weeks later a huge amounts of containers of a perfect shiny product - a perfect incarnation of the blueprint is thrown back over the fence to the engineer and sales of perfect products is skyrocketing like hell. "And they all lived happily everafter"
I'm neither from chemistry nor from big pharma but from R&D & scaling *not safety critical* electronic products. Let me phrase it like this: We researchers and engineers are naive and have no clue at all about the reality of (ultra) large scale production. Period.
An immense number of issues never thought of or foreseen by engineering to bee resolved and fixed by production teams. Engineers will quite often never receive any info about these issues.
So I would expect the same in pharma especially if its about ultra high scale and during a pandemie when literally millions of people die.
Clinical trials showed no issues but years later the super gau had happened:
"In the late 1950s and early 1960s, the use of thalidomide in 46 countries by women who were pregnant or who subsequently became pregnant, resulted in the "biggest man‐made medical disaster ever," resulting in more than 10,000 children born with a range of severe deformities, such as phocomelia, as well as thousands of miscarriages."
Root cause is a synthetic molecule which is synthetisised at the same time in the correct 3D orientation and in the mirrored 3D orientation (enantiomer):
"Different effect of (S)- and (R)-enantiomer
Sequence of racemization
The two enantiomers of thalidomide: Left: (S)-thalidomide Right: (R)-thalidomide
Thalidomide is a chiral compound that was sold as a racemate. The sedative effect is attributed to the (+)-(R)-enantiomer,[36] the fruit-damaging effect is attributed to the (-)-(S)-enantiomer"
It doesn't really work right? At least according to a review from Cochrane and the WHO.
Or at least: It doesn't really work as much as we hoped to?
So what happened? How come the drug that got approved by the FDA and which was used to treat the President of the United states no less is somehow close to worthless now?
And what is the likelihood that the same thing could happen to Paxlovid and Molnupiravir?
Has someone looked at it?
I am sorry my comment has more questions than anything. But judging the effectiveness of drugs seems to be a really really hard thing to get right (also considering the whole Ivermectin debacle).
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.
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.
> 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.
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.
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.
"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?
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.
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.
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.
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.
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.
It seems to me the same people who complain that they are being idiots for not doing something are the same folks who will complain when they do something and it blows up in their face. Tons of 20/20 hindsight, etc.
> I came away from the pushback convinced that nobody would ever believe the FDA was dragging its feet until I could make them read about it in flagro delicti - write a post saying the FDA is dragging its feet now, on this thing that you and I currently realize is obviously good.
Should be "in flagrante delicto" (https://en.wikipedia.org/wiki/In_flagrante_delicto). "In flagro delicti" means "in the whip of the crime".
Out of curiosity, does "stop the trial" mean "stop collecting data and give the drug to everyone in the control group" or does it mean "stop collecting data and stop giving the drug to anyone".
if it means the latter, then I fail to see how "it would be unethical to continue not giving to to the control group" makes sense, given that the potential control isn't getting it either way.
I'm uneasy with the elimination of a control groups by ending a trial early and giving the drug to the control group. They did this with the vaccine, too. Okay, it's hard to say no to the obvious humanitarian argument. Still, at the point when the control group is eliminated, all we've learned is that the drug seems safe and effective (for some p-value) in the short-term; we don't know anything about the long-term.
"Like everyone else, I hate the fact that pharmaceutical companies are the only people with enough resources to run high-quality studies, and that this controls what drugs we end up using."
For COVID the single most influential clinical trial in terms of drugs we are (and are not) using is RECOVERY - not a pharma led trial
It seems entirely reasonable to wonder why it ever had to be 'amateur hour' with ivermectin testing. Well, 'wonder' is not stating it genuinely. It seems entirely reasonable to observe that there was an obvious motive not to trial ivermectin with the same zeal as Paxlovid.
> I know I’m not going to convince many ivermectin supporters. So consider this: ivermectin is FDA approved. It’s approved against parasitic worms, but that’s fine: once a drug is approved for anything, any doctor can (more or less) use it for whatever they want. Doctors can absolutely prescribe ivermectin right now if they want, and many of them (like Pierre Kory) have. The ones who don’t prescribe it are avoiding it because they think it doesn’t work, not because the FDA is trying to prevent them.
False. You seem to be a bit removed from the situations hundreds if not thousands of patients have faced. Doctors even. Doctors getting placed on leave, fired, discouraged from prescribing Ivermectin. Even Pharmacists are banding together on /r/pharmacy saying they won't fill the prescriptions. Heck, Dr. Paul Mark, Front line critical care doctor, suing Sentara hospital in Virginia because Board of Directors wouldn't let him prescribe it.
Curious why people don’t feel the same sense of urgency about lives lost, say to lack of medical insurance, in this country?
Why didn't the pharmacy companies do these types of studies for Ivermectin?
It could also be FDA is playing the long game. The cost of a false positive for a drug approval is enormous as it erodes trust. So maximizing saved lives on a long enough of a time horizon could actually be withholding a drug that's virtually certainly good.
It could also be that it's bureaucracy in its worst. I don't know why they can't sit around the clock and do whatever they would do in six weeks in one.
I really admire someone who can think like this and write like this. Another great post!
Forgive me if this is a silly question, the first time I'd heard anything about Pavloxid was today. Which leads me to my question: why isn't this ALL OVER the news? I guess I would understand the FDA stuff flying under the radar, but there's not even a single headline letting anybody know that "Wildly Effective Covid Drug Has Been Discovered And Is For Real This Time"? Is it because of the chloroquine stuff? Is it because the Kyle Rittenhouse verdict just came out? Is it a coincidence?
I asked some friends who are progressive leaning peers at my fancy schmancy small liberal arts college, and they also had never heard of it.
I'm not familiar with this particular decision but when I was involved with a study that stopped early it was the DSMB that made the ethical decision. Are you sure it was the FDA that stopped the trial? If not, there is no ethical paradox. I for one wouldn't want the FDA to cede regulatory/ethical decisions to a heterogeneous collection of study boards of mixed quality.
"I honestly believe they’re operating on Fast Mode, well aware that the entire country is watching them and yelling at them to move faster."
Government bureaucrat time is not like human time. If i ran the zoo, I would have soldiers surround the FDA during the middle of the day, and I would tell them: "Free pizza and Coca Cola, but no one leaves until you have this nailed down."
The trial absolutely should have continued. It's already going to be hard enough to get some people to take the drug.
Soo...if this drug works this way - does anyone predict that they will roll back the vaxports and other casual removal of various rights for not getting vaccinated? Covid was never more than maybe 5 or 10 times more deadly than the flu. If this makes it 10 times less deadly then covid is just another version of the flu essentially. Will we have some two tiered society and somehow in 20 years you'll still be barred from certain jobs if you're not vaccinated against Covid?
In a country and world where tobacco and alcohol are legal and fast food is subsidised through things as varied as cash handouts to big ag, tax breaks or zero tax for companies, and profit friendly ultra low minimum wage levels below the poverty line... In a nation where we know that the people in charge really really care about us, but just can't bring themselves to ban tobacco when they are in the mood to start banning things and firing people 'for our protection'. Will they remove all the mandates and stop firing people for not getting a vaccine they don't need?
Or will vaxport authoritarian madness carry on and expand into a medical social credit system and you'll get fired for not getting a flu shot every year and covid boosters forever? Will you be banned from attending University? Will you be barred from jobs. Will you be disallowed from travelling internationally or across certain state borders? The new regime of restrictions will serve no covid relevant purpose and protect no one from anything, but that doesn't mean they would stop the McCarthyist era style blacklisting of people. Oh you didn't get your flu shot and it was due last week, sorry you can't come into our restaurant?
I'd be predicting that such measures will become entrenched and slowly expand like most other forms of power creep. No one had or needed passports 150 years ago, but now everyone has to use them.
On the other hand, the good news is Pfizer will never have a negative quarter ever again with those Booster profits coming in, even if they have a pay out a few billion more in lawsuits from their criminal behaviour which results in people dying. Things are looking up for the upper class who will be able to buy into some system to skip the queue for all that vaxport stuff just like they can skip all the patriot act airport restrictions through buying a VIP pass.
I'd put this at 80% confidence....with the failure mode for more centralised power expanding would be some early and rapid defeat in the courts while they try to roll out their authoritarian plans further and further. So almost 100% the government will try, but maybe 80% chance they'll succeed. It isn't like any meaningful number of the patriot act era rights removals were ever restored. Will China take over the US's global leadership role or will the US simply become China through a medical apartheid?
I believe that this latest trend in destroying the control/placebo group is terrible. While they argue that the net benefit to the (in this case 612 users) control group is too great to ethically continue, significantly more than 612 potential consumers wont trust the drug because of it.
I expect this will become the "status quo" in drug testing moving forward, and it will only be a matter of time until a major problem hurts a large population.
Speaking of predictions - anyone care to speculate what will happen once it is approved? Will anti-vaxers refuse to take it? Will its use get politicized? Will it end the pandemic so I can get my former happy life back?
A quick look at clinicaltrials.gov shows 11 studies, 7 still in progress, concerning PF-07321332/ritonavir. Some are designed to look specifically at plausible bad interactions with common drugs. It's nice if the efficacy trial with ~1000 patients doesn't show any random safety problems, but it would be malpractice to not complete the safety tests on plausible bad drug interactions before unleashing it into a population that's going to be using it together with 100's of other drugs. Would you approve a drug without even a small test on people with hepatic impairment?
Am I the first to notice that the name is too damn similar to the drug in the fiction series Firefly? The one with rather extreme effects not noticed unless after distribution? A rather poor name choice for something we want hastily approved.
https://firefly.fandom.com/wiki/G-23_Paxilon_Hydrochlorate
The basic point is clear. It's not just covid. Should trials of any drug be suspended before FDA approval? What is the decision point?
The argument that it is silly to stop the trial and then drag your foot with approval is strong (but there is a good comment below about the scaled up production process etc.).
But more generally, it sounds a bit polemic to me to speculate that the FDA is concerned with its reputation. Maybe at stake is not the reputation of the FDA, but the reputation of the approval process? Assume the case a drug is approved "prematurely" and saves 30000 lives but completely unexpectedly kills 10000 patients (who would otherwise have survived). What sounds like a great net positive outcome might still be very negative on the long term: Many people might lose trust in approved medication or evidence bases medicine in general.
Also, I am a bit surprised that Scott seems to use "expected value" so freely in this context. Medical ethics does not seem to work that way at all? At least, there seems to be a heavy asymmetry between action and non-action, maybe that is reflected in the approval system as well?)
How much is it worth for someone within the FDA to send this article to whatever the largest internal distribution list they can find is? Assuming they don't care about lives and just about being compensated for reputational damage, wondering whether lives * p(anything more happening | internal annoying emails) > happy price. Not re: me, I'd just do it. :D
"I care about maximizing expected lives saved more than I care about my reputation. Can the FDA say the same?"
Goodness, of course not. You're a mortal, with a finite influence and finite time, and by and by you will be replaced no matter what and your reputation will be of interest only to historians, at best. The FDA is immortal, and their reputation colors everything their future self does indefinitely. And it is actually *way* more important that generations of future Americans trust the FDA than that even as many as 50,000 lives in the present are saved -- because there are way, way more than 50,000 future lives at stake.
I'm not taking a position on how fast the FDA should approve this drug, but I am saying I think that your statement is too facile by half, and fails to acknowledge the importance of maintaining institutional trust[1] in an area in which people by nature have strong feelings. That is, and very well should be, a major priority at the FDA.
-----------------------
[1] I mean, would you even be feeling like you had to write a long screed on ivermectin, or fend off vaccine folklore, if institutional trust *hadn't* been lately damaged? Expensive, is it not, that kind of damage?
As an ivermectin supporter I just want to signal support for paxlovid.
As a conspiracy theorist, I do suspect it's just a rebranding of ivermectin (new molecule, same mechanism of action), but in any case, it Works! Let's use it! This isn't a left right divide, this shouldn't be any sort of X/Y divide, everyone likes paxlovid! Yay paxlovid!
This is really an asinine post. Why doesn't a regulator that chooses between life and death move faster and break things? The answer is inherent in the question. Calm down and let them do their jobs. When you push harder and criticize them, aren't you begging them to screw up? And at that point, your tune will change to griping about how they make bad decisions. Being a two-bit critic on the internet seems a lot easier than actually having responsibilities over human lives.
Realistically speaking, it's probably irrelevant whether they approve it now or in two months unless the drug has a very short shelf life, as they won't have enough of the drug to go around for a while due to having to work at ramping up production of it. Even if it was approved right now, I'm not sure if it would even save net lives.
They're probably using that time to make sure manufacturing is up to snuff and maybe looking over the data a few more times to make sure they didn't overlook something stupid.
The reason why we didn't immediately start mass inoculating people with experimental vaccines in 2020 wasn't because it couldn't save lives, it was that it could potentially cause serious issues with diminished trust if some of the vaccines didn't work, which could disincline people from taking the real ones.
The biggest downside of rushing out a medication is that it doesn't work and it erodes trust in future medications that do work.
A secondary question is, when will the FDA or the EMA (European medical agency) approve Sinovac, which by now has been used 3 billion times or so.
Probably when their boards are no longer as heavily Pfizer dominated.
The best moral argument I can construct for treating the control group and the population at large differently is that the control group has accepted some degree of risk in enrolling in the trial. Therefore they have provided the identical informed consent as the trial participants that are not control, while the population at large has not, and perhaps in some understanding of the facts cannot. The control group would in this argument not be morally equivalent to the population and low probability, yet-to-be discovered hazards can ethically burden the control group but not the population, assuming of course the control group has served their end in providing adequate data for the evaluation process.
I suspect the answer has more to do with some implicit assumptions about a difference between causing harm (active and specific) and allowing harm to take place (passive and diffuse). But that’s speculation.
I find it curious that some guy in his basement can legally sell a virtually untested LSD analogue online for months or years before the authorities get around to blacklisting it, but a company like Pfizer needs to wait for months for their drug to get whitelisted before selling any. So maybe the solution is for Pfizer to sell Paxlovid as a "research chemical" for home laboratory use :P
Many people have made the convincing riposte to this post that as manufacturing capacity will be the limiting factor, it doesn't matter that much how long (within reason) the FDA takes to approve Paxlovid.
I don't think this is as convincing as it first appears - Paxlovid isn't like a vaccine where you pretty much want everybody treated asap. So a country like the UK orders 200 million doses and tries to get the jabs into arms just as quickly as punters and jabbers can be lined up.
The antiviral will be given to vulnerable people, after infection and after symptoms develop. Which explains why the UK has ordered only 200 thousand doses. You only need as many doses as people who are getting sick (+ a few 'just in case', to be on the safe side)
My point is that supply may well equal demand, in which case delaying approval goes back to being a really bad thing to do.
I appreciate the bat post.
I see this as a big problem, that only big business has enough resources to fund good clinical trials, because like this only treatments that promise good profits get rood evaluations. If anyone has a cheap or easy treatment gets just to hear 'It's not proven to work/be save, so shut up when the professionals talk'. So it's no wonder the costs of our health systems raise so fast.
Perhaps it would be a great project for ACXG+/++ to fund independent research or trials of promising cheap and easy treatments that are therefore not interesting for commercial research.
One Candidate i came across could be chlorine dioxide solution (CDS) as described here: https://akjournals.com/view/journals/2060/107/1/article-p1.xml
Big takeaway is that Agencies do not design their procedures along cost-benefit lines, especially failing to consider the cost in time of the procedure.
Approval of Paxlovid sounds like a job for MINIPAX and MINILUV.
I'm sure I'm not the first to convey this sentiment, but I'm a little confused by this post. We all already know that with any governance system there is a trade off between centralization of authority - let's call it "having an X (e.g. medical, financial, educational) Tsar", in keeping with SSC tradition - and having lots of checks and balances in a more distributed system, which I'll call democracy (yes, I know democracy entails other things as well, it's just an ad-hoc term).
The more Tsar you go, you can act more quickly, be flexible as a society and respond to extreme changes in your environment. The down side is, if the Tsars themselves are human, they are prone to errors, corruption, or any other lapses of judgement, and can fail miserably. The more democratic you go, the more stable you are, with less chance for catastrophes of that sort, but unreactive and sluggish on the down side.
Current western society is not in the optimal point in this trad-off, probably a little too democratic. The way this manifests in reality is that the FDA will take six weeks to approve a drug that everybody agrees is effective. Not a year, mind you, six weeks, which to me sounds like a completely reasonable time to push papers hastily for a federal entity. And that's ok, cause what we earn by sacrificing speed is the up-side of a more democratic process (more insurance against huge errors).
So basically the entire point of the post can be summarized to "I wish we could move more towards the optimum, here's an example that makes this point very clearly." Well, yeah, but designing regime schemes is really hard. If we have a better solution to this (like earlier posts about the FDA) than awesome, let's discuss the solutions themselves and see how viable and effective they might actually be. If we don't, there's not really much to say.
Either way I'm not sure another example deserves its own post, and should, imo, be presented in the right context. Maybe a list of facts demonstrating how the US is too democratic (in the sense defined above) and not Tsar enough. Or just the FDA. Preferably, if there's also a list of opposite examples such that in time, we can try and compare the two.
Would be nice if stopping trials for this reason resulted in an immediate EUA. You can retract later if new data conflicts, but at least it's legal to use in the meantime.
"Perhaps there’s not enough evidence for the FDA to be sure Paxlovid works yet? But then why did they agree to stop the trial that was gathering the evidence?"
Researchers run on one system of ethics while the FDA runs on another.
I'm reminded of some old episodes of M.A.S.H where the main characters who were treating some injured POW's complained about the government not being able to decide whether they wanted to blow up these young people or put them back together in light of paying to do both.
Just popped by to say the word “manufacturing”, but I see Andrew beat me to it. Good show, Andrew!
" it’s pretty weird that the FDA agrees Paxlovid is so great that it’s unethical to study it further because it would be unconscionable to design a study with a no-Paxlovid control group - but also, the FDA has not approved Paxlovid, it remains illegal, and nobody is allowed to use it."
Possibly because Pfizer may have been a little bit naughty (allegedly!) in releasing all the data on their own vaccine trials, so the FDA are being careful not to simply rubber-stamp something a pharma company tells them?
https://www.bmj.com/content/375/bmj.n2635
FWIW, my wife was prescribed Ivermectin by her doctor recently (for something unrelated to Covid or worms) and basically no pharmacies in our (large metropolitan) area would fill the prescription.
The delay is explained by Parkinson's Law: work expands to fill the time allotted to it.
Problems with this approach: if followed, manufacturers could have an incentive to submit poorly designed studies and profit from the distribution until the application is rejected. This in turn will cannibalize the proper testing and development of effective treatments.
This piece also neglects that the monoclonal antibody treatment is available and people taking an ineffective medicine would be denied such treatment.
Finally, this piece misses a discussion of what goes into the approval process so one can identify which steps could be skipped and what the tradeoffs are.
"Heck, people can get ivermectin even without a prescription as long as they use the veterinary version."
—people have, and ended up in the hospital, due to the dosage being way different and marine also the inactive ingredients. If you're mentioning the vet version you should mention that
If they stopped the trial prematurely due to effectiveness, then it is 99% guaranteed that the FDA will approve the drug. The threshold is much lower than for vaccines because this drug will be given to people who are sick and at risk of severe disease.
The reason for the delay is most likely that it takes a lot of time for FDA to review all the paperwork. The approval process includes a lot of validation. It is not only the trial results but every step related to manufacturing and ending with labelling. The pharma company first need to develop the scaled-up manufacturing process, validate all assays to show that the manufactured drug is what it says it is, free from impurities and at correct active substance content. Document all these validations and then reviewed by the FDA who will probably request some corrections and changes. Unfortunately, it takes quite a lot of time.
I guess that the prediction market is mostly right and possibly insiders already know tentative date of approval anyway. Unless the pharma company had done this preparation work in advance (someone knows for sure), the market predicted date should be approximately correct.
for some context Re; Andre's update:
52 NDA - new drug applications are being held up due to a back log in the FDA conducting inspections of the sponsors (owners of the drug in question) and of the manufacturing facilities (not always the same as the owner of the asset). many biopharma companies use outsourced manufacturing - in many cases for both production of clinical trial materials & commercial products).
https://twitter.com/ZacharyBrennan/status/1462867968816300040
also, your PPS comment is provably false. There have been numerous cases in which hospitals have blocked the administration of ivermectin for covid patients - most notably in the recent case involving Dr Pier Kory's colleague Dr Paul Marik. Marik's case is interesting because it is not just IVM but all early treatments being prohibited by his medical administrators.
Also, the 'horse dewormer' propaganda campaign against IVM waged by the FDA, mainstream media among others is certainly an odd happening notably while the NIH confirms that IVM is being researched in clinical studies about its effectiveness against covid. a review of clinicaltrials.gov or the NIH's website confirms these facts.
Safe to say Scott sold out and also lost 30 IQ points.
Was leaning that way after the Ivermectin post and now I'm 100% sure.
Unsubscribed from this garbage.
typical Big Pharma, taking Louis C. K. away, but here, have Ali Wong
It does seem like there ought to be some sort of “we have no reason to think this doesn’t work, go ahead and use it at risk while we review the paperwork” pathway for active pandemics.
I mean, they are waiting weeks to just have the Zoom call to decide whether to give it an EUA. That’s insane.
From the outside, it does seem like reputation risk, as Scott mentions, is a big problem at the FDA. I can somewhat understand their point of view. If people lose trust in the FDA's actual decisions (beyond just the current groups of critics), rather than mostly critiquing their inactivity, I could see how they would believe that would be more damaging to their societal authority as a regulatory body. But more transparency is a better solution than dragging their feet and being opaque. I would propose they make faster decisions, even if they're sometimes wrong, and publish public post-mortems on decisions, good and bad, to show the public that they're paying attention to the process and seeking to improve it. I think FDA reform could give us faster action and a stronger reputation for the FDA, rather than trading those two off as the FDA seems to believe is the case.
"But then how come the prediction markets are already 90% sure what decision they’ll make?" -- this seems to say that the prediction markets think there's a 10% chance it won't be approved at all. 10% is a sizeable number, why are we all suddenly so dead certain that it needs to be treated as 0?
(My issue right now is that it seems like we would've observed short-term side effects already, and I'm not sure an extra month will let us observe any long-term ones -- but this might be a false dichotomy, I really don't trust my intuitions on this enough to start screaming STOP THE TRIALS ALREADY. The CFR for Covid is not humongous, so it doesn't take a hugely common side effect for it to have the potential of outnumbering the Covid death toll.)
"Molnupiravir is saving lives in the United Kingdom; the FDA is blocking it here.
"If clinical trial results are accurate, another antiviral pill (Paxlovid) reduces the risk of hospitalization and death among high-risk COVID patients by 89%. If other countries approve it first, patients will again lose precious time as the FDA denies them the right to access the drug on the strength of those approvals."
https://www.nydailynews.com/opinion/ny-oped-fda-fails-american-patients-20211109-d2zzig2ounflbgczympfwrtp3u-story.html
From prototype (trials) to ultra large scale production (a pill for billions of humans) typically it takes quite some time. The naive western imagination yet is that a clever engineer throws a blue print for any product over the fence to the factory - typically seen imagined as a cheap Chinese factory full of dumb human robots. Days or weeks later a huge amounts of containers of a perfect shiny product - a perfect incarnation of the blueprint is thrown back over the fence to the engineer and sales of perfect products is skyrocketing like hell. "And they all lived happily everafter"
Back to the reality of products, their development and scaling: its a mess and a hell (see "production hell" https://observer.com/2019/02/elon-musk-tesla-production-hell-podcast-interview/)
I'm neither from chemistry nor from big pharma but from R&D & scaling *not safety critical* electronic products. Let me phrase it like this: We researchers and engineers are naive and have no clue at all about the reality of (ultra) large scale production. Period.
An immense number of issues never thought of or foreseen by engineering to bee resolved and fixed by production teams. Engineers will quite often never receive any info about these issues.
So I would expect the same in pharma especially if its about ultra high scale and during a pandemie when literally millions of people die.
Just as a reminder https://en.wikipedia.org/wiki/Thalidomide_scandal
Clinical trials showed no issues but years later the super gau had happened:
"In the late 1950s and early 1960s, the use of thalidomide in 46 countries by women who were pregnant or who subsequently became pregnant, resulted in the "biggest man‐made medical disaster ever," resulting in more than 10,000 children born with a range of severe deformities, such as phocomelia, as well as thousands of miscarriages."
Root cause is a synthetic molecule which is synthetisised at the same time in the correct 3D orientation and in the mirrored 3D orientation (enantiomer):
"Different effect of (S)- and (R)-enantiomer
Sequence of racemization
The two enantiomers of thalidomide: Left: (S)-thalidomide Right: (R)-thalidomide
Thalidomide is a chiral compound that was sold as a racemate. The sedative effect is attributed to the (+)-(R)-enantiomer,[36] the fruit-damaging effect is attributed to the (-)-(S)-enantiomer"
So lets hope the best...
Can someone tell me what happened to Remdesivir?
It doesn't really work right? At least according to a review from Cochrane and the WHO.
Or at least: It doesn't really work as much as we hoped to?
So what happened? How come the drug that got approved by the FDA and which was used to treat the President of the United states no less is somehow close to worthless now?
And what is the likelihood that the same thing could happen to Paxlovid and Molnupiravir?
Has someone looked at it?
I am sorry my comment has more questions than anything. But judging the effectiveness of drugs seems to be a really really hard thing to get right (also considering the whole Ivermectin debacle).
I wonder if people taking benzos will be able to take this. The enzyme inhibitor they include in the drug is responsible for clonazepam metabolism.