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.
To expand on this more: the clinical trials only show that *that one particular batch* was safe and efficacious (the FDA thinks this, since they agreed to terminate the trial early). Pfizer must then show that the commercial batches will be identical in every relevant way to the clinical trial batches, so that they will have the same safety and efficacy. What are the relevant ways? Pfizer must decide that, and justify their decisions to the FDA with supporting evidence.
Scaling up chemical manufacturing is not trivial (a regular contender for Understatement of the Year). E.g. heating and stirring work differently in different sized reactors. Heat transfer in and out of your reactor works through surface area, but heat produced/consumed by the reaction depends on volume. If your stirrer design isn't right for the viscosity of the solution, you might get hotspots and so on.
Ideally, the FDA expects you to understand the chemistry so thoroughly that you know everything that can possibly go wrong, and design your commercial process so that none of these things can possibly happen. The commercial batches will therefore be identical *by design* to the clinical trial batches, and you have to prove this with science. Of course in practice you don't have to have collected all the evidence before you can start selling batches, but you must have your plan in place with a solid scientific justification for every decision you made along the way. It also helps to have made a statistically valid number of commercial batches to show that your beautiful process works as designed (how many batches is that? you tell me, and justify your decision).
Pfizer/Merck will have thrown everything at this problem alongside the clinical trials, as they can afford to do this, so their regulatory submissions will be pretty good. However they still might have to store the new batches for a few months to demonstrate that they have a comparable shelf-life to the old batches, and FDA might wait to see this data etc.
Note that this really only applies to new chemical entities; people have been manufacturing fluvoxamine for years and its probably well understood by now. Not always true though; we saw a worst-case situation recently with the ranitidine withdrawal: a medicine that some reasonably healthy people take every day of their lives was shown to be contaminated with small amounts of a nasty carcinogen. If Pfizer happened to have some gaps in their understanding for the Paxlovid process, the FDA might go easy on them as dying of Covid now is worse than a slightly increased risk of cancer in the future, but it takes time to review all of these risks and make a justified decision.
Ian E Fellows writes:
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.
This is a good point - though hard to square with the previous good point. 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?
A quick look at clinicaltrials.gov shows 11 studies, 7 still in progress, concerning PF-07321332/ritonavir [ie Paxlovid]. 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?
And to be clear, the phase 2/3 trial specifically excluded those plausibly bad situations, like "Known medical history of liver disease", "Receiving dialysis or have known renal impairment", or "Current or expected use of any medications or substances that are highly dependent on Cytochrome P450 3A4 (CYP3A4) for clearance or are strong inducers of CYP3A4".
Thanks for pointing out these other studies.
But a lot of this seems like non-emergency thinking to me. If it’s an emergency, you approve the drug with a black box warning saying “not tested in liver disease patients or drug-drug interactions yet, check back in a few months”, and then the 99% of patients who don’t have liver disease or use warfarin can get it.
But given that there are some reasons why the FDA might be holding things up even after the trial was clearly positive, I was wrong to say this was literally inexcusable. I will add an entry to my Mistakes page noting that I jumped to conclusions here.
But Dan Elton is still skeptical:
Dr. Marty Mackary 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."
Also keep in mind we are not talking about full approval here and the requirements for what needs to be in an EUA application is all stuff the FDA invented during the pandemic (the EUA legislation, https://www.law.cornell.edu/uscode/text/21/360bbb-3) only requires that "known and potential benefits of the product... outweigh the known and potential risks of the product"
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?)
I agree something like this is true, which is why my preferred solution is for the FDA to have different levels of approval. I would like them to immediately give this a medium-level approval, something like “we have reservations about this drug but it’s not technically illegal to take it”, and then update it to a high-level approval later on. Otherwise everyone’s life is going to be constantly held hostage to a PR campaign to sway the opinion of the stupidest 10% of the population.
Maybe a better way of framing this is that we made a deal with the devil when we decided to ban all drugs until a centralized government agency said they were okay. Now the entire reputation of Medicine as a field is inextricably linked with the reputation of that government agency, and protecting that agency’s reputation is more important than saving lives, having reasonably-priced drugs, making reasonably-paced medical progress, or basically anything else. I acknowledge this behavior makes sense given that the deal exists, but I think we should be looking for ways to extricate ourselves from it.
Highlights From The Comments On The FDA And Paxlovid