I think the especially weird thing is that in the historical analogy of AZT for AIDS, after the trial was stopped early, the FDA issued thousands of Compassionate Use Exemptions so that people could use the drug even while it was getting approved.
I explore that story here:
So why couldn't the FDA use this precedent?
One possible (but still IMO unlikely) reason delay isn't so bad: logistics of getting high risk people tested within 3 days of symptoms and getting them the treatment, are harder than we think, so Merck and/or healthcare providers are working on a way to roll that out easily.
The manufacturing argument can explain why the FDA wants some more time to check if the mass produced drug is as safe as the trial drug. But it doesn't explain why they would then stop the study. Presumably, Pfizer has already produced enough to finish the study. For the people in the study, having a 50% chance of getting life-saving treatment is unambiguously better than a 0% chance. And we get more data.
I love internet comments who know what they are talking about.
There is also an unfortunate tendency for people who are experts in one thing to assume that the experts in another thing are idiots. A random example might be a consumer electronics engineer talking s_it about automotive electronics engineers because they still do X. And the automotive engineer might say, "Yes, we could do it your way. If we were designing cars to be used indoors. We need products that work as well when parked outside all night in Alberta in January all they do when parked outside all day in Dubai in August." Ohhhhhhh....
I'm not sure if I buy the mass-production-check reasons given.
To be a big drug manufacturer, it seems like you must already have very robust post-production quality control processes in place, and these are going to look more or less the same for any drug. For each batch, pull X number of random samples, check that they look like the batch from the trial and that variances are sufficiently tight, etc. This process, while not foolproof, seems like it should at least easily be strict enough so that some extra perusing from the FDA will have no marginal utility. That is, if the problem is subtle enough to pass the pre-existing post-production QA check, it will be too subtle for the FDA to detect. (And of course the FDA could take random samples in real-time and run it through their own lab.)
Is anyone aware of a historical case where the drug company said "Hey, we're ready to go" and the FDA came along and said "Doh! Vat 76 in production line 4 has too much temperature variance"? I'm skeptical.
With regards to how well the manufactured drug maintains its efficacy in storage, it seems like a provisional approval could just include a requirement that the initial expiration date is no further away from manufacturing than those used in the trial.
This seems like an unusually fast turnaround time for highlights-from-the-comments. Or maybe it just seems that way because we got two such posts in short succession and I don't remember how long ago the Ivermectin post was.
This whole thread seems to be predicated on the misconception, from Scott on down, that this efficacy trial ( NCT04960202) is THE trial that will determine if the FDA can authorize / approve it. That is simply not true. There are 10 more, 7 ongoing, human trials registered at clinicaltrials.gov, each designed to test a different aspect of efficacy and (mostly) safety. NCT04960202 was the big efficacy trial, and passing that is a huge milestone in the approval process. (Sometimes you can rescue a efficacious drug that has some bad safety signals if you have a clear understanding of the harmful mechanisms, but I've never heard of of a non-efficacious drug that was brought back to life.) But, safety is still a big hurdle in the approval process. In addition to the registered human trials, there are dozens, if not hundreds, of animal studies, that you and I will never see, that also go into the FDA decision process. Nobody here has any idea what the results of those are. (OK, we know that not all the rats died, or the human trials would not have taken place, but there's a lot of room between there and "its as harmless as distilled water, or rainwater, and only pure-grain alcohol".) The results of all those studies runs to hundreds of thousands of pages, and anyone who claims FDA can go through all that in 24-48 hours without cutting corners is talking nonsense. Basically, the press release that comes after a good efficacy trial doesn't tell you much about the real state of the approval process, or when you should start grousing about the FDA dragging it's heels.
I seem to remember a post back in the SSC days where Scott complained that the FDA is loathe to rescind approval of a drug once it is given. That even fast-tracked drugs, approved provisionally based on surrogate endpoints, don't get pulled from the market after not doing the appropriate follow-up studies based on hard endpoints.
What's the probability that an emergency authorization of this drug will be approved, save some lives in the short-term, and then persist in medical practice for years before its use finally fizzles out? Will we save more lives on the near side of the distribution than we risk in the perpetual long tail?
And remember that trials stopped early on ethical concerns for the placebo arm consistently overstate efficacy - which is exactly what we would expect from the statistics. Not saying the efficacy isn't there, just that we should presume it's overstated based on the declared early end of the trial. Which takes a little from the sails of the argument for rushing it through a few weeks early.
Scott complains about the system we have, with some merit, but approval in the current system is what it is. A better system would allow tiered approvals like Scott suggests, but we're talking about approval the current system. Is there evidence of a strong - functioning - corrective mechanism post-approval? Or if this is a mistake, do we just have to 'live with it' from now on?
> 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?)
That's precisely the problem.
> I agree something like this is true, which is why my preferred solution is for the FDA to have different levels of approval.
Isn't this already true? There's one level of approval for "medicine" and a different level of approval for "supplements".
SSC has discussed the different levels in the past: https://slatestarcodex.com/2013/09/28/sleep-now-by-prescription/ https://slatestarcodex.com/2014/06/15/fish-now-by-prescription/
Where are the ritonavir supplements?
Thanks for the post, and the highlight :) Regarding your question:
> We know that Pfizer has already started making the drug; is it possible they can run the factories
> now, the FDA can examine the factories while they’re running, and then the FDA can retroactively
> pronounce that the factories are fine and people can use the drug they produced?
In short, yes. The FDA calls this "Concurrent Validation". Quoting from here: https://www.fda.gov/drugs/guidances-drugs/questions-and-answers-current-good-manufacturing-practices-production-and-process-controls#5
"... after having identified and establishing control of all critical sources of variability, conformance batches are prepared to demonstrate that under normal conditions and operating parameters, the process results in the production of an acceptable product. Successful completion of the initial conformance batches would normally be expected before commercial distribution begins, but some possible exceptions are described in the CPG. For example, although the CPG does not specifically mention concurrent validation for an API in short supply, the Agency would consider the use of concurrent validation when it is necessary to address a true short-supply situation ..."
An Emergency Use Authorisation would be another exception. If you can put your hand on your heart and say "I believe these batches will be ok, based on this data I have" then the FDA will listen. They will review your data for themselves though, before giving you the go-ahead, and that is probably whats going on right now for Paxlovid.
Dr. Marty Mackary [sic] says this : "As a Johns Hopkins scientist who has conducted more than 100 clinical studies and reviewed thousands more from the scientific community at large, I can assure you that the agency’s review can be done within 24 to 48 hours without cutting any corners."
I remember reading this when it came out, and I'm not sure it's credible. I suspect the 24-48 hours is an estimate for an academic review, not a regulatory review. I don't have any knowledge of the FDA's internal processes, but normally a regulator can't just say "looks good to me", they have to file hundreds of pages of reports demonstrating that every item was scrutinized and considered.
In the short term, the pills may do more harm than good: if we start with a limited supply, it would make sense to prioritize the pills for the unvaccinated, since they are much more likely to have severe outcomes. If this becomes a part of the pill allocation process, it would look super awkward, as if we are punishing the vaccinated for doing the right thing. If some people are on the fence about getting the vaccine, knowing that getting vaccinated might hurt their chances of getting the pill might push people towards not getting vaccinated, and if this happens to a significant degree it could outweigh the benefits of a limited supply of the pills.
Read a piece published today in Stat about challenges and obstacles anticipated in deploying Paxlovid and molnupiravir, including remaining questions about how diagnosis may impact when and whether they can be prescribed: https://www.statnews.com/2021/11/23/covid-antivirals-pandemic-game-changers-americans-struggle-access/. It sounded like answering these questions from a regulatory standpoint might be a major contributor to the time needed for the FDA to approve Paxlovid - because it sounds like they need to issue guidance on whether a PCR positive Covid test is needed, or for which populations it may not be, or if it can be prescribed later than three days post-symptom onset (because the study only covered how well it works when given within three days of symptom onset). One person quoted suggested that the drug(s) be authorized for prescription some immunocompromised people preemptively in response to Covid exposure without a positive diagnostic test. But with only the data available from the studies at the time of the FDA meeting, it sounds like the FDA needs to be able to issue guidance on all these things, many of which which are not directly answered by study data alone (and ideally make the guidance mostly feasible for real-world conditions where e.g. Covid testing turnaround time may not be very fast). Am I correct in assuming this is a major contributor to the time to approval in this process? These seem to pose a real challenge (given real-world limitations in distribution of and access to the drug, as well as safety considerations - even if you had unlimited supply, the cost/benefit ratio for preventative prescription of Paxlovid for Covid exposure or suspected Covid might not pan out in all populations just because post-diagnosis treatment does) that consumes time for reasons other than bureaucracy just takes time because it has to take time even in emergencies.
This is exactly what makes me so mad about arguing on these issues. The same people who defend the legal regime that totally bans drugs which the FDA hasn't yet found to be sufficiently beneficial (tho often claim to believe there is a constitutional right to autonomy which lets women choose to abort babies, which I love the idea of but surely that creates some similar right to take unapproved potentially lifesaving meds) then use the worries about lack of trust to justify being extremely reluctant to approve anything.
It's a vicious bootstrapping which seems largely based in the inability to imagine that people could adjust to any other message. Sure, now we may equate FDA approval with certain features but there is no reason the FDA couldn't wake up tomorrow and tell ppl only green boxed meds are tested to that degree and (with a bit of PR) most ppl and doctors would adapt.
>Scaling up chemical manufacturing is not trivial (a regular contender for Understatement of the Year). E.g. heating and stirring work differently in different sized reactors. Heat transfer in and out of your reactor works through surface area, but heat produced/consumed by the reaction depends on volume. If your stirrer design isn't right for the viscosity of the solution, you might get hotspots and so on.
>Ideally, the FDA expects you to understand the chemistry so thoroughly that you know everything that can possibly go wrong, and design your commercial process so that none of these things can possibly happen. The commercial batches will therefore be identical *by design* to the clinical trial batches, and you have to prove this with science. Of course in practice you don't have to have collected all the evidence before you can start selling batches, but you must have your plan in place with a solid scientific justification for every decision you made along the way. It also helps to have made a statistically valid number of commercial batches to show that your beautiful process works as designed (how many batches is that? you tell me, and justify your decision).
>Pfizer/Merck will have thrown everything at this problem alongside the clinical trials, as they can afford to do this, so their regulatory submissions will be pretty good. However they still might have to store the new batches for a few months to demonstrate that they have a comparable shelf-life to the old batches, and FDA might wait to see this data etc.
I do not understand why the FDA would be concern itself with the details of the manufacturing process when they can just require a chemical analysis of a representative sample of the product.
I get that for mRNA vaccines, this may be insufficient because you also have to check the size of the lipid nanoparticles and that the mRNA is actually within them, but for the Paxlovid, Wikipedia suggests that the active ingredient PF-07321332 is just a straightforward organic molecule.
I am not a chemical engineer, but between mass spectroscopy, chemical analysis (for isomers) and in vitro testing (?), I feel that modern age chemistry might be up to the task to decide how identical two pills are two each other.
I feel the selection of a process of manufacturing should just be a business decision: giving a probability estimate of a certain process chain to fail and ruin your bunch, optimize for maximum expected gain, or something.
The same goes for the shelf life. If the pills are sufficiently identical to the trial ones, I would assume that their shelf life is similar as well. All the counterexamples I can think of feel rather constructed, like "We replaced Phosphorus 31 with P-33, now our chemical has a half-life of 25 days" (and skipped mass spectroscopy, and also the chemical costs three orders of magnitude more) or "we put H2O2 into the filler material, and given time, it reacts with the active ingredient over time" (so the pills were obviously not chemically identical).
If the product is easily chemically analyzed, it should be enough to regulate the product: When I buy table salt, I do not really care if it comes from sea salt or the salt mines or from someone burning sodium in a chlorine atmosphere.
Only if the product is a complex mixture of different chemicals regulating the process chain makes sense: a complete microbiological analysis of a representative sample of soy burgers out of ever freezer is not cost effective, so we mostly regulate the manufacturing process, cold chain, and use-by dates and sample only sporadically.
I feel standard chemical drugs (e.g. not mRNA vaccines or the like) are mostly the NaCl case, not the soy burger case.
That is not to say that upscaling the synthesis of new chemicals is easy, only that trial and error should be a valid strategy. Any new drug even moderately effective against COVID-19 stands to make billions. If the manufacturer has to throw away the first few millions of doses because the selected process did not work, this should not affect their bottom line too much beyond the added delay to market.
"Maybe at stake is not the reputation of the FDA, but the reputation of the approval process?"
This but cynically. Every time the FDA drags its feet part of me thinks that they're protecting the reputation of their insane bureaucratic obstructionism. If they ever let a high-profile pill through with less than six weeks of meetings and nothing terrible happened, people might start to wonder why we're paying so many bureaucrats to sit in so many meetings.
The only reason I'm not convinced this is what's going on is that it implies people pay enough attention to the FDA to notice what they're doing.
Since you took a lot of trouble to come to a numerical conclusion about Ivermectin, I'm curious how certain are you that the FDA's Paxlovid approval process will cost tens of thousands of lives. Eliezer Yudkowsky writes as if he thinks it's 100%, or at least very close to that... https://twitter.com/ESYudkowsky/status/1462960741049200643
I have the impression that one major function of the FDA is to shield prescribers from liability. If the FDA says something is safe under X conditions, then you can't be sued if you prescribed it under X conditions and something went wrong. If the FDA says something is efficacious for Y, then you can't be sued if you prescribed it for Y and nothing happened.
Tort is not great. It seems like a good thing to be able to hold doctors accountable for mistakes and biases that cause health damage, but at best Tort adds friction and conservativeness to healthcare, and at worst it aids bad actors and hurts good ones.
But when I try to think about how to fix tort, one of the first ideas I have is tort insurance. But it seems like private tort insurance would be really hard, and public tort insurance...would look very very similar to the FDA.
And it's not clear that multitiered FDA approval would be able to preserve this tort insurance feature.
I think the idea that Scott and others (Marginal Revolution, I think) have put forward of having more gradations of FDA "approval" is a promising one. Is anyone working on finding Congressional sponsors for legislation that would do that?