Fads, Foolishness, and Why We Need the FDA

I think most of us know that our president has turned into a drug pusher of sorts. Like many of us, he longs for a silver bullet to save us from Covid-19. With no solid evidence to rely on, he started a PR campaign to encourage the use of hydroxychloroquine, the anti-malarial drug used by patients with lupus and rheumatoid arthritis. “What do you have to lose?” he asked in one of his daily press briefings. He encouraged medical first responders to take the drug as a virus preventative, a use for which there is zero evidence. Then he bragged that the federal government had stockpiled 29 million doses and was sending it “all over”.

What’s wrong with that? Frankly, a lot of things. We need to let the scientists tell us what works and what doesn’t, and they need to find out by doing gold standard clinical trials – meaning randomized controlled trials (RCT). In an RCT, participants are randomly assigned to receive either the treatment under investigation or, as a control, a placebo or the current standard treatment. (In the case of Covid-19, there is no current standard treatment). To unpack what an RCT is: randomized means the patients are randomly assigned to one of the treatment groups; controlled means that in addition to the treatment arm, there’s a control – placebo or standard treatment – arm for purposes of comparison). If the study is blinded, the researchers don’t know who is in which group while the study is going on, which should eliminate cherry-picking healthier patients for a trial and other forms of results-skewing bias.

A lot has gone wrong with early attempts to figure out whether hydroxychloroquine is helpful in treating Covid-19:

· early studies conducted in China were too small for the data to have much validity

· studies have been confounded by other variables, including other treatments given to patients in a desperate effort to save them

· studies have lacked control arms

· scientific protocol has been so poor that a French study that got a lot of people excited was subsequently revoked by the scientific journal that published it

Fortunately, numerous RCT studies whose results are more likely to be valid and reliable are underway. When smart doctors see mediocre data, they usually reserve judgment and say they look forward to when reliable data are available. When politicians with urgent agendas see mediocre data, bad stuff can happen. For instance, Elon Musk and Paul Sperry’s pro-drug tweets went viral. Fox News told its viewers that hydroxychloroquine was the equivalent of a great new elixir. Breitbart picked up the story and flogged it some more. President Trump climbed on the bandwagon.

Hydroxychloroquine isn’t the only drug that’s being touted by non-scientists. Rudy Giuliani has tweeted about a stem cell treatment for Covid-19, and went out of his way to undermine the FDA while doing it: “The general reputation of the FDA – and I don’t mean to be critical at a time like this – but it is very slow,” he said. More disturbing, he implied that if the FDA actually does its job, which is to ensure drugs are tested for safety and appropriate dosages, that’s an unforgiveable impediment that can result “in unimaginable loss of human life.” In other words, the FDA shouldn’t do the job for which it was created and on which Americans rely.

A major problem is that untested or inadequately tested drugs can maim or kill. We learned this decades ago with thalidomide, which killed the unborn and caused babies to be born with malformed limbs. Even drugs that have been studied can be unsafe and may need to be recalled, as in the case of heart attack-causing Vioxx. We do have off-label prescribing in the U.S., at the discretion of physicians, but there’s a fine line between smart prescribing and reckless experimentation on the American public.

When we go through our standard three rounds of human clinical trials (often preceded by a round on lab animals, though animals and humans usually react differently to drugs), the process takes time even when fast-tracked. But we have much better odds of being safe. We absolutely need to go through the process with vaccine development for Covid-19, as some vaccines – think vaccines studied for SARS, HIV, and dengue fever – have made the disease worse.

If we skip RCT trials, we are throwing science and caution to the wind. As two doctors recently wrote in an article in the Journal of the American Medical Association, what’s gone on with hydroxychloroquine and other drugs that have received Emergency Use Authorization (EUA) from the FDA is this: “[M]any clinicians are embarking on ill-advised and uncontrolled human experimentation with unproven treatments.” In other words, sick Covid-19 patients become guinea pigs because of a fad driven in part by popular media, public fear, and politicians.

I am not opposed to “compassionate use” of an experimental drug for desperately ill patients. At a certain point, it should be up to the patients and their families whether to take certain risks. But there are potential harms if we give in to political pressure to use unproven drugs. Starting with lesser harms and moving toward greater ones, we have:

· The occasional bad egg of a doctor. Case in point: The Southern California physician selling treatment packs on-line, advertised as a “100% cure”, a preventative, and a “concierge medicine experience”. Step right up and get your family four-pack for $3,995. You get hydroxychloroquine and azithromycin AND, as an added bonus, anti-anxiety medications so you can feel calm while you swallow medications not approved for Covid-19. (You also get to find out that your prescribing physician is up on federal charges and may face a long jail sentence for false advertising.)

· Doctors and dentists prescribing the drug for themselves and their families.

· A black market for the drug. Counterfeit drugs. Fraud.

· Life-threatening heart arrhythmias in a small subset of patients who take hydroxychloroquine.

Possible immune suppression. And, if you look up information provided by the manufacturer, Sanofi, you see that the drug commonly causes: blurred vision, nausea, abdominal pain, diarrhea, vomiting, headache, skin rash, and anorexia.

· Shortage of a vital medication for patients with lupus, malaria, and other life-threatening conditions who take hydroxychloroquine for their illnesses.

We need our federal health agencies – including the FDA and the CDC – to be science-driven and apolitical. These agencies make mistakes, as we’ve been learning, but they perform crucial roles. If the FDA suddenly grants Emergency Use Authorizations for unproven and risky medications, the intention might be good, but the appearance might be that the agency is succumbing to political pressure.

If we want to save our sick, we can hope for a great drug to prove useful (I’m keeping an eye out for emerging data on the anti-viral remdesivir and a few other medications), but what we really need to do is prevent, track, study, and keep working on the antibody and vaccine studies. We can start ramping up our vaccine production capacity now even though we aren’t sure which type of vaccine technology is going to prove best. Think how frustrating it will be if we suddenly have a great vaccine but no one – and I’m thinking especially about the federal government – has invested in scaling up the capacity for mass production and dissemination. We can see the probable future, so let’s build it. While we’re at it, let’s hold in mind that the World Health Organization is the entity best positioned to organize the response when Covid-19 does in under-resourced and less wealthy countries what it is currently doing to us. Let’s learn from the mistakes of the recent past and create the future for which we will be grateful.

(Postscript: Since I drafted this essay, the Veterans Administration contributed data to a preprint study revealing that hydroxychloroquine not only didn’t keep patients off ventilators – it contributed to a higher death rate. More study data will surely be forthcoming.)

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