Research Translation Podcast

When readers sent me media articles touting baloxavir (‘Xofluza’), I started looking. In the interim, Sensible Medicine, a wonderful Substack by evidence-based doctors, published a podcast, and today a written piece, recommending the drug. I believe they have it deeply wrong. Fun! Check it out, tell me what you think. When I was seven years old I tried hard to see through a frosted glass window. My pediatrician, a silly and smiley man with a nasal voice, stood behind me. “You see that, across the street?” he quacked. Then, leaning forward, as if to sync his line of sight with mine, “See?” His hand was on my shoulder, squeezing gently. I squinted, and tried hard. “Wait… is that it?” “Ah, forget it” he said, smiling at my mother. “You missed it.” Which was true—I’d completely missed the shot in my shoulder. Research Translation is fully reader-supported. Like it? Consider becoming a paid subscriber to help me keep doing it. In addition to being a beloved and brilliant pediatrician, Dr. Gribbetz was a master of distraction. Unfortunately, that’s a skill drug company scientists have also mastered—for different ends—and they played it to perfection with a flu drug called baloxavir. In recent weeks The Atlantic and the Wall Street Journal, noting the rough flu season and weak effects of this year’s vaccine, ran articles extolling the virtues of baloxavir, a single-dose drug hoping to replace 5-day Tamiflu. Both media articles rely heavily on experts who have fallen hard for a 2018 trial published in the New England Journal of Medicine. To be fair, the study also convinced FDA reviewers who approved the drug. Though clearly, that ain’t tough, and the study is a crowded swamp of data. Reading it feels like trying to see through frosted glass. I’ll try to be efficient here, but for the geeks I’ll get into more detail on the podcast. The ‘study’ is actually two separate trials. One compared three doses of baloxavir to a placebo. The other compared baloxavir vs. Tamiflu vs. placebo. Which is remarkable because Tamiflu is a debunked drug, years ago revealed by many independent investigations as not just unhelpful but, to some critics, a premeditated fraud. As I’ve written and podcasted before, Tamiflu trades side effects for flu symptoms, adding as much misery as it subtracts, while failing to prevent serious illness. Meanwhile, symptoms—the only measure either drug even claims to affect—were identical with baloxavir. So the first and most obvious headline should be: BALOXAVIR WAS NO BETTER THAN TAMIFLU, A PROVEN FAILURE. That should end all discussion. But it won’t. The most interesting quirk about the baloxavir paper is that the first trial is an “FDA, Phase 2, dose-finding study”—a fancy way of saying it was done to find a dose, not prove efficacy. The trial had three drug groups of differing doses, plus a placebo group. And no group, when compared to placebo, had enough participants to say whether the drug works. That isn’t a flaw, it’s the point of Phase 2 studies. But it means efficacy claims drawn from them are, by definition, a mistake. Why? Because with three drug groups and one placebo, the drug is getting multiple shots on goal. Efficacy trials get one shot on goal—no more. Ever. And that’s why Phase 2 studies are, well, phase 2. Only Phase 3 studies can say whether a drug works. And in fact, it's weird to publish two studies of different design, from two separate FDA phases, together. It’s weird because the studies have different goals and are interpreted differently. Which is deeply distracting. So what were readers being distracted from? The paper’s much more pivotal Phase 3 study compared baloxavir to Tamiflu and placebo. And here’s where a red flag pops up, bright and tall: Why wasn’t the study a non-inferiority trial comparing the two drugs? ‘Non-inferiority’ is a special design statistically and methodologically focused on finding equivalence between drugs. That’s different from a classical superiority trial, designed to find a difference between drugs. For years non-inferiority has been the FDA’s favored design for testing when a new drug claims to be as effective as an older drug. Typically, in such cases the new drug offers some convenience upgrade, like being a pill instead of an injection. Or, perhaps, 1-day versus 5-day dosing. Like baloxavir. Baloxavir is a picture-perfect candidate for a non-inferiority study, but that’s not what the company did. Which means they probably expected more than equivalence with Tamiflu. They expected superiority. When that failed, they settled for (and pretended to celebrate) sameness. How can we know the trial aimed to show baloxavir was better, when the authors claim superiority based on dose-finding, placebos, and virologic results? The Methods section is the paper’s guilty conscience, confessing. The researchers used classical (non-parametric) superiority testing techniques to compare the drugs. Besides this, there is circumstantial evidence. For starters, early lab studies found baloxavir had better effects on viral load and biologic markers than Tamiflu. But that only matters when it translates into people feeling better or being safer, which didn’t happen. This probably surprised and dismayed company researchers, who—like the literati of medical evidence—surely know that Tamiflu is a failed drug. So when baloxavir failed, they changed the narrative: “It’s as good as Tamiflu—yay!” And sadly, most flu ‘experts’ are experts in virology, but not evidence. So when the red flag appeared—a failed superiority trial dressed up as success—they did what seven-year-olds do when asked to see through frosted glass. They squinted, nodded, and missed the shot. Tamiflu is a failed drug. Now we know baloxavir is too. Moreover, both represent a profound risk to public health, because both must be started within two days of first symptoms. If everyone with a sniffle runs immediately to their doctor, or ER, or clinic—resources already dangerously over-burdened—people in dire need of these resources will be harmed. So as I’ve written and podcasted about before, if you want one day’s relief from the flu, try silicon nasal sprays. They’re better, safer, and cheaper, and they’re over-the-counter. Get full access to Research Translation at researchtranslation.substack.com/subscribe