Last year, researchers testing cheap generic drugs in the hope that one or more of them could prove to work as a Covid-19 treatment came across a promising candidate: the antidepressant. fluvoxamine.
In a massively randomized controlled trial, called Togetherresearchers at McMaster University compared eight different recycled ones drugs and found most of them – including ivermectin, the antiparasitic agent that many embraced as a Covid-19 miracle cure – failed to do much against the disease. But fluvoxamine appeared to reduce serious illness by about 30 percent. While fluvoxamine had already shown something promising in minor trials last yearsmall-scale trials can sometimes show false good results, so most people did not take fluvoxamine seriously before the impressive data from the Together trial.
“This already feels different from hydroxychloroquine and the company given the high quality of the research,” Paul Sax argued in NEJM Journal Watch, which analyzes recent research. “We may finally be inside something.” However, government regulators remained more skeptical – in part because the regulatory system is not exactly designed to add new indications for drugs that have already been approved by the FDA without a pharmaceutical company sponsoring them.
Another researcher who was convinced of the fluvoxamine case, David Boulware, decided to take matters into his own hands. The FDA did not know how to handle applications for a drug that had to be approved for a new indication without anyone responsible for the submission? Lived. He would submit it yourself. In December, he wrote and submitted an emergency application for fluvoxamine as a treatment for Covid-19.
In many ways, it was a heartwarming story about the power of civic science. But that was not the case.
This week, the FDA rejected the application for an emergency use of fluvoxamine. Regulators argued that the results of the Together study were more ambiguous than they appeared – most of the benefits came from a reduction in extended observation in the emergency room, an endpoint that is quite specific to the clinical setting of the study in Brazil and not necessarily as useful. . They pointed out that since the Together trial, further studies have attempted to find a record of the benefits of fluvoxamine, and for the most part, they have not found such great results.
In an unusual move, the FDA published an explanation for the rejection, and for the most part it is very reasonable. But the whole episode still shows what has been broken about how we review and approve drugs.
The game of drug approval
For eight months, the National Institutes of Health, which maintains an updated database of research findings on Covid-19 treatments, did not update the fluvoxamine page with information on the new, promising studies. (NIH informs about that side today, as it has done over the past year, that “There is insufficient evidence that the COVID-19 Treatment Guidelines Panel (panel) can recommend either for or against the use of fluvoxamine for the treatment of COVID-19.”)
That frustrated researchers, especially last winter, when omicron cases began to grow, and the best treatments for Covid-19, such as Paxlovid, were not widely available. Many of them told me that with results like these, the FDA would approve a drug that had a drug company that supported it, and that what worked against fluvoxamine was what they considered its biggest benefit: that it was cheap and well known.
To be clear, fluvoxamine was already approved by the FDA – for obsessive-compulsive disorder (OCD). This means that doctors can prescribe it in any context they think is appropriate, and it is often prescribed off-label for anxiety and depression. It could also be prescribed off-label to Covid-19, but many doctors are not willing to make such off-label prescriptions. For this reason, proponents of the drug wanted the FDA to determine that fluvoxamine is also indicated for Covid-19, so treatment for the disease would be officially added to its listed uses along with OCD. But many experts were skeptical.
“I do not think the FDA will ever approve it for Covid,” Eric Lenze, co-author of Some early research on fluvoxamine, told me in December. “The reason the FDA will never approve it for Covid is exactly why it’s so useful to Covid; it’s cheap, and it’s widely available. Nobody can make money on it, so nobody wants to spend the money on it. to appeal to the FDA for approval. “
“The guidelines are far too conservative because they have not yet approved fluvoxamine,” said Ed Mills, one of the leading researchers in Together-case, told me in November. Why did the FDA not give fluvoxamine the same review that it would give other drugs? “They do not know how to handle submissions where no one is responsible for it,” Mills said. The process of adding an indication is generally initiated by the drug developer, whose lobbyists work closely with the FDA to ensure that they submit the evidence that the FDA wants to see approved.
Fluvoxamine research had been largely funded through Quick grants, a private philanthropic effort to make Covid-19 research work, and since the drug is generic, no one would make money on its approval of Covid-19. “It’s very disappointing as a scientist to see that it’s actually not about clinical evidence, it’s about lobbying,” Mills told me.
The FDA’s rejection announcement this week made their thoughts clear, and it’s clearly not all about lobbying.
It is important to note that the crucial rationale for fluvoxamine as a treatment is much weaker now than it was last winter when Boulware filed the application. At that time, there was a severe shortage of effective Covid-19 treatments that could be taken at home instead of in the hospital. Monoclonal antibodies, the first line of treatment in previous waves of the pandemic, did not work well against omicron. Many other therapies were only recommended for inpatients. There was no simple pill a person could take at home while their case was mild to prevent development to serious illness.
Today there are: antiviral drug Paxlovid. Even the strongest proponents of fluvoxamine agree that Paxlovid works much better – it seems to reduce serious illness by 80 to 90 percent. And even though Paxlovid was scarce this winter, there are plenty of doses in the United States today – even though many sick Americans still having trouble accessing the drug due to lack of primary care physicians they can talk to while far too many physicians remain misinformed about when to prescribe it.
But Paxlovid is not a panacea and it would still be good to have more options in our portfolio. “There are effective therapies available. But not everyone has access to them. Not everyone can tolerate them. Some people have contraindications,” Boulware argued in response to the FDA rejection. “And if you go anywhere else in the world, low- and middle-income countries, they have no access to therapy.” Still, it weakens that Paxlovid, which is a significantly better option, is now widely available, the case for fluvoxamine in the US, although countries that do not have Paxlovid access should probably do their own calculation.
On the whole, the FDA’s decision to reject the EUA for fluvoxamine seems reasonable – even to me, someone who has been enthusiastic about the research that supports fluvoxamine. However, the decision still highlights a lot that needs to be improved on how the FDA makes and communicates decisions about Covid-19 treatment.
Our Covid-19 processing error
For much of the pandemic, if you tested positive for Covid-19, the public health authorities advised that you should do nothing unless your symptoms worsen. Until recently, the official CDC page about what to do if you are sick with Covid-19 only advised you to wear a mask, wash your hands and clean high-contact surfaces to avoid infecting those around you. If your breathing worsens or you show signs of serious illness such as confusion or inability to stay awake, the CDC advises you to go to the hospital.
The CDC recently added an infobox highlighting that if you are at high risk for serious illness, treatment may be available. But for people who are not categorized as high risk – which includes older adults or those with medical conditions – the recommendations still do not include any treatment options.
Initially, the lack of treatment recommendations was likely because the evidence for any treatment option was rather weak. Early in the pandemic, treatments such as hydroxychloroquine were hyped, but did not work. Later, ivermectin was embraced as a miracle cure. (It is not.)
But the lack of treatment options was also the result of a process that was not very good at identifying them and communicating this information to a confused public. The fluvoxamine clinical trial – and many other clinical trials of potential treatments – were funded by private philanthropy because public processes were too slow to trust. The NIH’s official recommendation pages, which were to summarize the research status of various treatments, were often months out of date; I wrote in November 2021 that the fluvoxamine site had last seen an update in the previous April.
And instead of the FDA proactively working with researchers to establish clinical trials that the agency would be willing to rely on to recommend or discourage drugs, researchers had to design and perform trials themselves, and then some doctors had to fill out the EUA application for to get the FDA to look at the work they had done.
Right now, the need for fluvoxamine is limited, the evidence is mixed, and the FDA’s decision not to recommend the drug is quite reasonable. But ideally, the FDA would have been actively involved in the research process as soon as fluvoxamine first showed promise, and the government would have participated in designing and funding more definitive trials instead of waiting for a submission from an interested group of citizens.
The fact that the evidence for fluvoxamine is still uncertain at this time is a good reason not to issue an EUA – but it is also a sign of an obvious failure in our system to investigate promising Covid-19 treatments. Covid-19 is going to be with us for a long time, and other pandemics may be on the horizon. The process of developing treatments – and communicating with the public about them – needs to be improved.