Yesterday, the US FDA responded to a submission for Emergency Use Authorization (that was submitted 146 days earlier) for use of fluvoxamine "for the outpatient treatment of adults 24 years and older...to prevent progression to severe COVID-19 and/or hospitalization" (p. 2).

The FDA's conclusion is:

Due to limitations in the available clinical study results for fluvoxamine in the proposed patient population, lack of compelling in vitro and in vivo data to support the proposed [mechanism of action] of fluvoxamine for the treatment of mild COVID-19 disease, and context of increasingly available therapies with well-characterized [mechanisms of action] and consistent efficacy results in nonhospitalized patients, the FDA cannot reasonably conclude that fluvoxamine may be effective for the treatment of COVID-19. As such, FDA has determined that the criteria for issuance of an EUA are not met at this time.

While the FDA has concluded that the existing clinical data are insufficient to support the issuance of an EUA, these data suggest that further clinical investigation may be warranted. (p. 24, emphasis mine)

Personally, I'm disappointed. I've supported the fluvoxamine trials with my personal dollars, and directed more funding from the FTX Foundation to the same trialists for other drug trials (which I remain very, very excited about). But the most productive thing to do with that disappointment is to dig in to the FDA's reasoning in their decision, and decide what's to be done next regarding fluvoxamine.

Important note: This post isn't speaking for the FTX Foundation, the TOGETHER Trial team, the fluvoxamine EUA application team, or anyone but myself in my personal capacity. The FTX Foundation has funded the TOGETHER Trial and committed to additional funding in the future, but I don't have (and won't discuss) any information about fluvoxamine or the past fluvoxamine trial beyond what's available in the FDA decision memo and/or public elsewhere.

(1a)

While "the existing clinical data are insufficient" is sometimes used as polite euphemism for "there's nothing here, go home", it's clear to me that that's not what it means here.

In the submission, the primary endpoint was "long emergency-room visits (>6hr), hospitalization, or death", which gave a 95% frequentist confidence interval of [-48% to -12%] (pp. 12–13).

But the FDA didn't like the inclusion of long emergency-room visits ("To support an EUA, the FDA recommends proportion of hospitalizations and/or deaths...as the primary endpoint" (p. 12)). When you exclude those long emergency-room visits, you get a 95%CIs of [-41% to +4%] for "hospitalization or death", [-41% to +5%] for hospitalization, and [-62% to +26%] for death instead (pp. 14).

The basic FDA rule is you have to excude +0% in the 95%CI, and so nope, no authorization for fluvoxamine.

(1b)

Is "no authorization for fluvoxamine" the right call? I dunno, man.

One can argue about whether long emergency-room visits are worth reducing (I think yes, even just to keep you from using a bed that someone else might need), but the FDA says "there are uncertainties about the assessment of this endpoint and whether the 6-hour timepoint represents a clinically meaningful threshold" (p. 15).

One can also argue that a drug with a 95%CI of [-41% to +4%] against hospitalization or death should be the sort of thing we give people in an ongoing medical emergency, but it's well-understood that the rule is the 95%CI has to exclude +0%.

Would I want my doctor to give me off-label fluvoxamine if I had Covid-19 inflammation that might land me in the emergency room for >6 hours? Yes, obviously.

Should the FDA emergency-authorize fluvoxamine for "the outpatient treatment of persons >24 years of age with positive test results of SARS-CoV2 viral testing to prevent progression to severe COVID-19 and/or hospitalization"? (p. 2) I dunno; I think the FDA should authorize more things than it does in general, but not authorizing this one seems consistent with choices it makes elsewhere.

The obvious thing that should happen next, of course, is that the world should see another wave of clinical trials studying fluvoxamine, which don't stop until the FDA's preferred endpoint excludes +0% at p<0.05 (or the results start to look much worse). That will take a few million dollars and a couple of months, and then a couple more months for another FDA review. People will be hospitalized and die because of the delay, but that's the way everything works in this space.

(2a)

In the cost-benefit analysis, the FDA mentions the "context of increasingly available therapies with well-characterized [mechanisms of action] and consistent efficacy results in nonhospitalized patients" (p. 24), specifically listing remdesivir ($2,340/course), paxlovid ($529/course), monoclonal antibodies ($1,200-$2,000/course), molnupiravir ($707/course), and convalescent plasma (not cheap) (pp. 4-6).

Meanwhile, ICER estimates that fluvoxamine costs $12/course.

Look, $529 for a course of paxlovid might be a better deal than $12 for a course of fluvoxamine. $529 for a course of paxlovid might be better than a free course of fluvoxamine. The protease inhibitor does do a better job at preventing hospitalization and death than the anti-inflammatory drug, and stopping those additional hospitalizations and deaths could well be worth $517/course.

To put the cost in context, if 20% of the US population needed a course of paxlovid, that would cost $35bln; I'm sure the US government can find the cash somewhere.

(2b)

On the other hand, if 20% of sub-Saharan Africa needed a course of paxlovid, that would cost $120bln, and I'm not so sure that that money will get found.

Now, the FDA isn't supposed to be in the business of regulating pharma products for Africa, or Latin America, or anywhere but the US. Statutorily, they can't be. So the feasibility of a drug that costs hundreds of dollars per treatment shouldn't really be weighing on their analysis if the extra hundreds of dollars are in fact worth it, and there are millions of paxlovid courses "increasingly available" (which seems basically true of the US).

But if that's an explicit part of the decision context here (as it appears), then it raises the question of whether FDA authorization should be the standard that the rest of the world looks up to (as it often is). For similar reasons, it raises the question of whether US/Europe-based trials should be the default assumption in infectious disease, if the FDA isn't the right regulator for Latin America, or sub-Saharan Africa, or...

Even if paxlovid is "increasingly available" in the US, it may remain scarce and prohibitively expensive in many other places around the world, and perhaps other countries will need their own drug regulators to make their own cost-benefit analyses -- and potentially different decisions -- based on the actual situation they face.

(3)

I titled this post "round 1" because it's clear that, unless efficacy numbers see a huge shift, additional trial data evaluating fluvoxamine against placebo are going to address the main issues that the FDA raises in the decision memo. Now that it's clear what endpoint will be in play in an FDA review, the TOGETHER Trial team can re-insert the fluvoxamine arm into the adaptive protocol, let it run until the "hospitalization or death" endpoint comes out with p<0.05 significance, and send the application back in.

It will be interesting to me what decision the FDA makes at that point -- will the "context of increasingly available therapies" lead them to decide that an accessible drug that's merely 20-30% effective in keeping people out of the hospital has no place in the US? Or does fluvoxamine get put on the EUA list -- perhaps for people who have a contraindication from paxlovid due to the ritonavir inclusion?

If the FDA rejects again because fluvoxamine is less effective than other (dramatically more expensive) drugs with well-characterized MOAs, will other regulators from countries where those drugs aren't accessible then take a different stance?

I, for one, hope to find out at least some of these questions.