The battle against Covid-19 has been marked by false hope, as too many people embraced would-be cures like hydroxychloroquine and ivermectin only to have rigorous studies fail to show the drugs had a benefit.
One lesson is to only trust the most rigorous studies, known as randomized controlled clinical trials. But an equally important one: We need to get much better at conducting these rigorous studies more quickly and cheaply — and that goes beyond the Covid pandemic. This is not just a problem of science, but of infrastructure.
Last week, a clinical trial called TOGETHER produced two potentially important conclusions: A little-discussed experimental drug called peginterferon lambda cut in half the number of Covid-19 patients who ended up going to the emergency room or hospital. And the much-discussed antiparasitic drug ivermectin failed to prevent hospitalization for Covid patients at all.
TOGETHER, like the RECOVERY study conducted in the United Kingdom and REMAP-CAP, conducted basically everywhere but the United States, was a platform study, a streamlined clinical trial that evaluated multiple medicines at once and that use a common placebo group. It’s from these platform studies that doctors have learned perhaps the most about Covid-19.
Edward Mills, the co-principal investigator of TOGETHER and a professor of health research methods, evidence, and impact at McMaster University, puts it a bit less gently.
“The only trials that have given us useful information during the pandemic have been the platform trials,” Mills told STAT in an interview, also citing the PRINCIPLE trial, which showed an inhaled steroid could reduce complications, and the PANORAMIC trial, which is starting in India.
“The people running those trials are all folks that for a number of years have been promoting this and banging their heads against walls and nobody listened until shit hit the fan,” Mills said.
Of course, some big traditional studies done by drugmakers did have a big impact — in particular, the vaccine trials. But it was RECOVERY that delivered the news that hydroxychloroquine did not help hospitalized patients and that dexamethasone did.
The TOGETHER results are less certain. The study showed promise for a fluvoxamine, an antidepressant, as a treatment to keep newly diagnosed Covid patients out of the hospital, but the results were not strong enough to lead to wide adoption. The results for peginterferon lambda, made by a small biotechnology firm called Eiger BioPharmaceuticals that currently expects to make only 300,000 doses by the end of the year, were just made public last week. The ivermectin results were first reported by the Wall Street Journal; the full data should be published in the coming weeks, Mills said.
But there’s no arguing these small trials, which were comparatively inexpensive, delivered huge amounts of information. RECOVERY cost less than $10 million. Mills said the budget for TOGETHER was also $10 million. And it didn’t come from the National Institutes of Health, a big drug company, or a major charity.
Instead, one of the major funders of the trial so far has been Patrick Collison, co-founder of payments firm Stripe, who Forbes estimates to have a $9.5 billion fortune. New funds are coming from the charitable foundation FTX, a cryptocurrency exchange, and its founder Sam Bankman-Fried, who is worth $24 billion, also per Forbes.
“One of the big questions is where are the big players in this?” asked Mills. “Where is Gates Foundation? Where is NIH? Where is Wellcome Trust?”
There can be downsides to the leaner trials, which often use what are called adaptive designs to assign patients to different medicines based on changing odds of success. They can sometimes give results that are less clear. One test will be what happens when regulators at the Food and Drug Administration get a look at the peginterferon lambda results.
Drug companies tend to want to avoid studies that allow their medicines to be compared so easily to one another, Mills said; he said neither Pfizer nor Merck want to allow other trialists to test their Covid pills. Pfizer said it is focusing its efforts in a way that maximizes the overall supply of its pill, Paxlovid. Merck said it is working to define when it would provide investigators its drug, molnupiravir.
It’s hard to deny that efforts like Mills’ point to a way to gather medical information faster and more efficiently than was possible before.
The best way to get real-world evidence would be to find ways of doing trials faster and cheaper. Martin Landray, who ran the U.K.’s RECOVERY study, has started a nonprofit aimed at taking that trial’s methods beyond Covid. Perhaps the whole pharmaceutical industry should be looking for ways to follow suit.
“I think pre-pandemic nobody knew how badly organized medical research is, and we assumed the esteemed investigators and big name universities or NIH would have systems in place about how to move rapidly,” Mills said. “It turns out they didn’t.”