Longtime readers (and I do mean longtime readers) might remember that I (as well as some of our other regular bloggers) have had our differences with Shannon Brownlee and Jeanne Lenzer. The most dramatic example occurred a decade ago during another pandemic, the H1N1 pandemic, when Brownlee and Lenzer wrote a really bad article about the H1N1 influenza vaccine in The Atlantic entitled “Does the Vaccine Matter?” They were referring to the frantic effort to vaccinate people with the newly developed H1N1 vaccine. It’s rare that an article provokes a response from more than one or two of us at SBM, but Brownlee and Lenzer’s article provoked responses from Mark Crislip, Peter Lipson, and myself, as well as a certain friend of the blog, while actual public health researchers were none too pleased, either. The reason I mention this is because, although Brownlee and Lenzer often go a bit too far in their assertions that we are all “overtreated”, when they are on point, they’re really on point, as in an article published last week in Issues in Science and Technology, “Pandemic Science Out of Control”, and I’m giving credit where credit is due. Of course, the way I like to say it is that we’re not just dealing with an infectious disease pandemic, but we’re also dealing with a pandemic of pseudoscience, misinformation, disinformation, and political propaganda that risks making the pandemic far more deadly than it would otherwise have been.
Theirs is a long (!) summary of the sorts of things I was trying to say last week about the dangers of bypassing science- and evidence-based medicine during a pandemic, using the example of hydroxychloroquine and azithromycin. Given that another example of (possibly) playing fast and loose with EBM occurred last week with the experimental drug remdesivir, I saw their article as a perfect time to expound a bit more on what I had written last week. Even if Brownlee and Lenzer do cover some of the same cases that I did, including Didier Raoult’s terrible science on hydroxychloroquine and azithromycin, promotion of these drugs by doctors like Dr. Vladimir Zelenko, whose incompetent “case series” tells us nothing about the efficacy of his drug cocktail, and “Dr. Phil” and Dr. Mehmet Oz, among others.
Global pandemics, a century ago and now
Brownlee and Lenzer begin with a callback to the last global pandemic as bad as the one we’re experiencing now, the 1918-1919 influenza pandemic, showing how, the more things change, the more they stay the same, or at least how some things don’t change very much, even over a century:
On September 14, 1918, in the midst of the worst pandemic in modern history, an article in the New York Times quoted Dr. Rupert Blue, then surgeon general of the US Public Health Service. Blue reported that doctors in many countries were treating their influenza patients with digitalis and the antimalaria drug quinine. There was no evidence that the two drugs were any more effective than folk remedies being used by patients, including cinnamon, goose grease poultices, and salt stuffed up the nose, but doctors were desperate and willing to try just about anything. They would eventually abandon quinine and digitalis as treatments for flu when studies showed they were not only ineffective but caused serious and sometimes deadly side effects.
Today, just shy of two months since the World Health Organization declared COVID-19 a pandemic, the media are once again flooded with cures, patients such as Michigan State Representative Karen Whitsett are being quoted with claims that hydroxychloroquine “saved my life,” and doctors are prescribing drugs that have not been shown to be effective. Only this time, it’s the twenty-first century, the age of “evidence-based medicine.” Or so it might seem. But instead of no science to back up treatments, we now have bad studies being reported uncritically in the press, and Twitter storms of doctors, journalists, and researchers arguing about the ethics of withholding drugs from dying patients, even though we have no idea if those drugs do more harm than good.
I discussed the case of Karen Whitsett three weeks ago (which today seems like ancient history), because she was in the local news a lot here in Michigan before President Trump picked up on her case and started touting it as “evidence” that hydroxychloroquine works against COVID-19. You can read the article linked to for a longer explanation, but the Cliffs Notes version is that her claim that hydroxychloroquine cured her seems highly implausible given that she claimed to start feeling better within a couple of hours of her first dose after she had been ill around 12 days, which is around the time one would expect recovery, given that that’s well within the parameters of the typical time course of symptomatic COVID-19 illness for people who recover. There were also oddities, such as her having used hydroxychloroquine to treat chronic Lyme disease, a fake diagnosis beloved of quacks.
Still, I was struck by the similarity between 1918 and now, at least in terms of doctors frantically trying to repurpose every drug under the sun that might be used to treat victims of the pandemic, regardless of whether there existed good evidence or not that the drugs being tested were likely to work. We like to think that we’ve progressed so much in the last century, and we have in many ways. Sadly, though, in our desperate response to a pandemic, physicians now share much in common with physicians then:
If there is a silver lining to all the confusion, it is that this pandemic is exposing three persistent fault lines in medicine. First is the willingness on the part of clinicians to abandon the prime dictum of medicine, to do no harm, and rush into treatments that not only may not work but may well cause serious harm. The fact is, most physicians are not trained to recognize good science from bad. Nor do they have the time to analyze every study, and too many are willing to ignore the need for reliable evidence when fear sets in. Even in non-pandemic times, doctors often favor treatments that have long been in use, seem biologically plausible, are highly remunerative, or have been heavily marketed by manufacturers. In the case of two drugs now being used against COVID-19, hydroxychloroquine and remdesivir, there is a very real possibility that patients who might have recovered from the virus without them will be harmed or even killed by the treatment.
The second issue exposed by the pandemic is the role the media invariably play in hyping science and the physicians who purvey it without regard to the quality of the underlying studies. Some reporters are acting out of ignorance. They know less about good study design than the doctors they quote. Others report on faulty research because it is their business to hype the stock of drug and biotech manufacturers, which have been known to release spurious results of studies when those results favor their products. Whatever the reason, stories in the media help shore up claims of miracle cures made on the basis of poor-quality research.
Since I’ve already beat the topic of hydroxychloroquine to death on this blog, I won’t say much more about it, other than that Brownlee and Lenzer do a generally good job of describing the shortcomings in Raoult’s studies, in particular his first one, while his second and third studies were basically uncontrolled case series that were very much uninformative. Meanwhile, Raoult was once again all over French media over the last few days, sounding very Trumpian while promoting himself, denigrating and bullying his critics, and generally portraying himself as a scientific genius, whom other doctors and scientists just can’t understand.
The press, politics, and opportunism
While it’s very much true that, as Lenzer and Brownlee point out, the media have a malign role in hyping bad science and the opportunistic fame seeking (and sometimes grifting) physicians who promote it (something we’ve been discussing on this blog for many years and a characteristic of the press that’s been amplified greatly during the pandemic), this time around there’s another element: Politics. As you might know, the narrative surrounding hydroxychloroquine was hijacked early on mainly by allies of President Trump, who trumpeted Didier Raoult’s bad science in late March, ultimately leading to the FDA issuing an emergency use approval for hydroxychloroquine on March 31. Meanwhile doctors who have no idea what they are doing when it comes to clinical research were touting personal case series so flawed that it’s impossible to draw any conclusions from them. The most famous of these is Dr. Vladimir Zelenko, a NY physician who claims to have treated hundreds of COVID-19 patients with hydroxychloroquine, azithromycin, and zinc, with incredible results and whose claims have been promoted by President, Laura Ingraham on Fox News, and many other Trump allies.
As Brownlee and Lenzer describe it:
Another study that received attention in the press was conducted by a New York physician, Vladimir (Zev) Zelenko, who claims to have had “100% success” treating 699 patients with a cocktail of hydroxychloroquine, azithromycin, and zinc. His miracle cure is being touted on social media, but Zelenko’s results are even more suspect than Raoult’s. For one thing, most of his patients weren’t even tested for coronavirus, making any claims that he’s curing COVID-19 meaningless. For another, Zelenko’s study was not randomized and had no placebo control arm. Those 699 patients who improved on his drug cocktail may have done no better than patients who got usual care—assuming they even had the disease. Zelenko, like Raoult, also skipped the process of submitting his study for peer review; he took it straight to President Trump’s personal lawyer, former New York City mayor Rudolph Giuliani. Giuliani in turn shared the study with the president and tweeted “Hydroxychloroquine has been shown to have a 100% effective rate treating COVID-19.”
As I like to say, whenever a physician claims “100% effectiveness”, my skeptical antennae start twitching mightily. Nothing in medicine is 100% other than that we will all die someday of something. In any event, I discussed Dr. Zelenko’s incompetence at doing anything resembling a valid clinical trial on SBM and elsewhere. So, based on no good evidence and in spite of the fact that there was evidence that hydroxychloroquine probably didn’t work and could cause harm in the form of dangerous, even fatal, heart rhythm disturbances, the FDA still issued the EUA, and, as Brownlee and Lenzer mention, this could be the consequence:
Whatever the reason for the FDA’s decision, the result is that 40% of physicians, many of whom have neither the skills nor the time to do their own critical appraisals and need to trust the FDA, say they have prescribed the drug for patients with COVID-19. Some physicians are even hoarding it in case they or family members are infected. Others are denouncing colleagues who urge caution, among them Anthony Fauci, the head of the National Institute of Allergy and Infectious Disease and the most prominent member of the White House Coronavirus Task Force. On an emergency medicine email list, one physician said, “By the time everyone gets their evidence together in a nice controlled study COVID will have packed its bags and left town with thousands dead.” On Twitter, Carole Lieberman, a psychiatrist from Beverly Hills, wrote, “People r dying NOW so no time 4 studies #Fauci wants!”
I’m sorry to say that the hospitals where I have privileges made hydroxychloroquine the de facto standard of care, based on anecdotal evidence, unpublished case series, and, truth be told, hype. They’ve since backed off, as has the University of Michigan, and most other academic medical centers, as physicians saw no evidence of efficacy but were observing evidence of toxicity. The bottom line is that hydroxychloroquine probably doesn’t work against COVID-19. At least, that’s the way the evidence appears to be trending.
Hydroxychloroquine is not the only example of bad science that was hyped by the media and used for a political purpose. Indeed, there’s also been a pandemic of armchair epidemiologists confidently spouting off about infection rates and case fatality rates, people who self-assuredly say, “I’m not an epidemiologist or infectious disease expert, but…” and then proceed to opine about the incidence, prevalence, and treatment as though they were experts. Personally, whenever anyone starts out by saying, “I’m not an infectious disease expert or epidemiologist, but…” I respond, “You should have stopped after ‘I’m not an infectious disease expert or epidemiologist’.” The problem, of course, is that estimating, for example, prevalence of exposure to COVID-19 and case fatality rates is very difficult in the middle of a pandemic in which there is insufficient testing, case numbers are still climbing, and the antibody tests likely have high false positive rates, and if you don’t have any training you don’t even know what you don’t know. For example, over the last couple of weeks, two doctors/entrepreneurs running a small chain of urgent care centers in Bakersfield, CA have been all over Fox News and other right wing media sources promoting their claim that COVID-19 is not only not more deadly than the flu but is in fact five times less deadly than seasonal flu, based on this video press conference:
Based on their “study” Drs. Erickson and Massihi have found themselves falsely elevated to the status of “experts” in the right wing COVID-19 denying crankosphere. They are in fact pseudoexperts. For one thing, from what I’ve been able to tell, although Dr. Massihi is a board-certified in emergency medicine, Dr. Erickson, who does all the talking in the first video, can’t even be viewed as an expert in emergency medicine, as he appears not to be board-certified in it based on my searches. For purposes of discussing epidemiology, it doesn’t really matter if Drs. Erickson or Massihi are boarded in emergency medicine anyway. In fact, Erickson and Massihi’s video, it turns out, is a slick mix of statements, made by doctors that are mostly true mixed with misinformation and bad science thrown together to give a message that is probably true (COVID-19 likely has a case fatality rate considerably lower than estimates made early in the pandemic) but exaggerated (it’s as low as influenza), all in service of a political message (“we should reopen America because COVID-19 is not that dangerous”).
Erickson starts out by describing how the focus on COVID-19 means that a lot of people with other medical problems, such as heart attacks and the like, are afraid to come to the hospital (or their urgent care clinics) and may be dying at home or recovering without treatment that might have minimized the damage. This is true. Erickson also notes that we should quarantine the sick and not the people who are well, which is, of course, the way we will eventually have to remove the restrictions, while dismissing the current approach of in essence “quarantining” everyone with shelter-in-place orders as overkill. The problem is that to be able to quarantine the sick and allow the well to go about their business with lesser restrictions, we need accurate testing, a lot more accurate testing. Absent a lot of testing, and the robust ability to trace the contacts of those identified as having COVID-19, the only option was the one that most nations and most states in the US chose: Shelter-in-place orders of varying strictness. While Erickson is correct that a more targeted approach to quarantine is desirable, he barely mentions what is needed to achieve that.
At this point, Erickson states that Accelerated Urgent Care centers have tested 5,213 people and that 340 of them were positive, which he characterizes as “6.5% of the population” of the Central Valley in California, their catchment area around Bakersfield. He then mentions that 12% of the tests in California were positive and 39% in New York were positive, after which they make a really brain dead extrapolation. Based on California’s population of 39 million people, if 12% tested positive then 4.5 million people in California might have had COVID-19. This is, of course, utter nonsense. Similarly, Erickson extrapolates from his observation that 6.5% of their COVID-19 tests were positive that 6.5% of the people in Bakersfield have or have had COVID-19; i.e., about 58,000 cases, far more than the 700 confirmed cases in the area thus far. He then makes the argument that hospitalization and case fatality rates should be based on these numbers, estimating the COVID-19 case fatality rate to be around 0.02%, arguing that it’s five times less lethal than the 0.1% case fatality rate due to the flu.
Finally, based on the “analysis” by himself and Dr. Massihi, Erickson identifies a number of economic and political implications, the most prominent of which, unsurprisingly, echo the COVID-19 diminishment and denial machine’s call to “reopen America” based on the argument that the shutdown is doing more harm than good. (They also make a really brain dead claim about the harm shelter-in-place is supposedly doing to our health. More on that later.) As several, including Dr. Jennifer Kasten, have pointed out, these two armchair epidemiologists made such an obvious mistake that they should be (but won’t be) embarrassed. They assumed that the population they tested, which were primarily symptomatic patients given that they had announced in March that they had lots of COVID-19 tests and would be testing patients suspected of having COVID-19, was representative of the population in their urgent care centers’ catchment area. So there was almost certainly enormous selection bias. After all, who comes to urgent care clinics to get a COVID-19 test? Obviously, it’s those who were worried that they had been exposed to COVID-19 or who had COVID-like symptoms, such as cough, fever, and shortness of breath. Far more of their patients at their urgent care centers would be likely to have COVID-19 than the general population. We also don’t know the time frame during which they were doing these tests, so the percentage of the population with COVID-19 could have been rapidly increasing.
This TV news report could easily have spurred anyone with symptoms or concerned that they had been exposed to someone with COVID-19 to head on over to an Accelerated Urgent Care center location to be evaluated and tested. And guess what? In that video, they state that only symptomatic patients would be tested. Is it any wonder that they observed a high percentage of COVID-19 positive tests? Dr. Erickson also makes the claim that sheltering in place at home harms the immune system because it encounters fewer pathogens, which is utter nonsense. I liked Dr. Kasten’s retort:
UNLESS YOU LIVE INSIDE AN AUTOCLAVE, YOUR HOME IS PLENTY PATHOGEN-RICH
The world is absolutely teeming with microbes. You’re coated in them, your house is coated in them, they enter your body with every breath you take and everything you eat. Your immune system is getting a perfectly adequate workout. You’re just restricting your exposure to a handful of things (respiratory pathogens) for a very short period of time.
One also can’t help but note that both of these doctors are big time Trump supporters and that Dr. Massihi had videos by antivaccine leader Del Bigtree linked to on his Facebook page before apparently deleting the posts. In any event, so egregious was this not-so-dynamic duo’s behavior that American College of Emergency Physicians (ACEP) and the American Academy of Emergency Medicine (AAEM) issued a joint statement condemning their promotion of misinformation.
This brings us to remdesivir.
Remdesivir, hype, and concerns about last week’s study
Brownlee and Lenzer discuss the state of the evidence regarding remdesivir, an experimental antiviral drug made by Gilead Sciences that had originally been developed to treat Ebola but found not to be effective, as it existed when their article was published:
Now the press and medical communities have turned their attention to remdesivir, an experimental biotech antiviral drug that has never been shown to be effective for any disease. The University of Chicago recruited 125 people for two trials, including 113 with serious symptoms of COVID-19 for a study sponsored by Gilead Pharmaceuticals, the manufacturer of remdesivir. The news outlet STAT obtained a video of researchers at the university reporting on their results to colleagues. STAT quoted Kathleen Mullane, an infectious disease specialist overseeing the studies, as saying, “The best news is that most of our patients have already been discharged, which is great. We’ve only had two patients perish.” The story also quoted Slawomir Michalak, a 57-year-old factory worker who was among the study participants, saying, “Remdesivir was a miracle.” Gilead’s stock shot up when the story broke.
STAT, in its breathless coverage, failed to emphasize that the University of Chicago studies, along with other Gilead-sponsored trials that are running simultaneously, are not randomized and have no placebo control arm. As Mullane even told her colleagues, without a randomized placebo control there is no way to know if the drug works better than no drug at all.
Yes, this was another single-arm study, and at the time of publication the only existing study of remdesivir in humans was a single-arm study published three weeks ago in the New England Journal of Medicine. This was peak COVID-19 publishing, when an uncontrolled case series of patients with severe COVID-19 treated with remdesivir under compassionate was published in a super high impact journal like NEJM and made headlines as a result. Be that as it may, the case series examined 61 patients with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing room air or who were receiving oxygen support. They received a 10-day course of remdesivir, consisting of 200 mg given intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. (Remdesivir is an intravenous drug.) The authors reported clinical improvement in 68% of evaluable patients. Unfortunately, the case series also did not collect viral load data to confirm potential antiviral activity in humans or any association between declines in viral load and clinical improvement. Basically, when you get right down to it, this study was not really much better than Didier Raoult’s latest crappy studies of his hydroxychloroquine/azithromycin combination in terms of telling us if remdesivir has activity.
Ironically, on the day after Lenzer and Brownlee’s article was published, two things happened. First, a randomized, double-blind, placebo-controlled study of remdesivir in COVID-19 patients from China was published in The Lancet. Eligible patients were adults admitted to the hospital with laboratory-confirmed SARS-CoV-2 whose symptoms had lasted less than 12 days before enrollment and who had an oxygen saturation on room air of 94% or less or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less (another measure of hypoxia), and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir at the same dose as the NIH trial touted by Dr. Fauci or the same volume of placebo infusions for 10 days and were permitted concomitant use of lopinavir–ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined at the time from randomization to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. An intention-to-treat analysis was carried out.
Basically, this was a negative trial. Of the 255 patients screened, 237 met the eligibility criteria, and 158 were assigned to the remdesivir group, with 79 assigned to placebo control. Unfortunately, remdesivir treatment was not associated with a shorter time to clinical improvement, and mortality was not different between the two groups. Subgroup analysis looking for hypotheses found that there was a trend towards a shorter duration of symptoms (not statistically significant) in patients treated with remdesivir who had had symptoms for less than ten days. Most disappointingly, there was no detectable difference in viral load between the remdesivir groups and the placebo controls. Again, basically this was a negative study with only the barest hint that remdesivir might—I repeat, might—work if administered earlier in the course of COVID-19. Those results, of course, were not at all encouraging.
On the same day, the National Institute of Allergy and Infectious Disease (NIAID), led by Dr. Anthony Fauci, issued a press release about a study of remdesivir in moderately ill patients:
Hospitalized patients with advanced COVID-19 and lung involvement who received remdesivir recovered faster than similar patients who received placebo, according to a preliminary data analysis from a randomized, controlled trial involving 1063 patients, which began on February 21. The trial (known as the Adaptive COVID-19 Treatment Trial, or ACTT), sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is the first clinical trial launched in the United States to evaluate an experimental treatment for COVID-19.
An independent data and safety monitoring board (DSMB) overseeing the trial met on April 27 to review data and shared their interim analysis with the study team. Based upon their review of the data, they noted that remdesivir was better than placebo from the perspective of the primary endpoint, time to recovery, a metric often used in influenza trials. Recovery in this study was defined as being well enough for hospital discharge or returning to normal activity level.
Preliminary results indicate that patients who received remdesivir had a 31% faster time to recovery than those who received placebo (p<0.001). Specifically, the median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group (p=0.059).
More detailed information about the trial results, including more comprehensive data, will be available in a forthcoming report.
In a press conference, Dr. Fauci was quoted thusly:
“What it has proven is that a drug can block this virus,” the National Institutes of Health’s Dr. Anthony Fauci said.
“This will be the standard of care,” and any other potential treatments will now have to be tested against or in combination with remdesivir, he said.
As you can see, the difference in mortality was not statistically significantly different, although that could just be because of inadequate numbers. It’s also very important to note the part about the adaptive trial design of this trial, which puts Dr. Fauci’s comment about how remdesivir will become the “standard of care” going forward into the proper context. In this particular trial, multiple different drugs can be compared to placebo or standard of care. The idea is that, if a signal of efficacy is found with one drug, that drug becomes “standard of care” and the trial is adapted to study how adding other experimental drugs compares to the “standard of care.” So what Dr. Fauci meant was that, based on the finding, going forward remdesivir will become the “standard of care” arm for the trial and the experimental arm will become remdesivir plus another experimental therapeutic. However, given that the FDA is on the verge of issuing an emergency use authorization for remdesivir to treat COVID-19, it looks as though remdesivir will become standard-of-care in general soon.
On Twitter, there was a lot of chatter about this study, in particular by Wallid Gellad:
Since NIH remdesivir trial is in the news…
— Walid "Confounding by Indication" Gellad, MD MPH (@walidgellad) April 29, 2020
And James Heathers:
Here's Fauci talking about it. Give him a listen, sharpen your ears at about 0.30.
"The primary endpoint was the time to recovery, namely the ability to be discharged."
He's right, it was.
On April 16th.https://t.co/U6Cx3XSOJ6
— 🏴James Heathers 🏴 (@jamesheathers) April 30, 2020
I’ll summarize, so that you don’t have to scroll through a Twitter thread if you don’t want to. As James Heathers and Waller Gellad noted, the original primary outcome of the trial when it was registered on March 20 was an 8-point severity scale (death, on ventilator, hospitalized with oxygen, all the way down to discharged with no limits on activity) but was changed to time to recovery. There’s still a similar scale for the secondary endpoints, but no numbers for that were reported. (Any bets on whether the results are negative?) This change was apparently made on or around April 16. I must admit that it did look very fishy to me. Endpoint or outcome switching, particularly late in a clinical trial is a huge red flag to me. Don’t get me wrong. There can be legitimate scientific reasons to switch primary endpoints of a trial, but they have to be really well justified. Gary Schwitzer has a good roundup of the criticism and questioning of the trial here.
I remain very suspicious that the NIH study was announced the same day that a negative study out of China of remdesivir was published. It just seems too…convenient. Maybe I’m being overly suspicious. Maybe I’m falling prey to conspiracy mongering. However, in the Trump era, when the Trump administration has politicized previously (mostly) apolitical government agencies as never before, it’s hard not to wonder, especially in light of Gilead’s increasing lobbying, if politics intervened.
Amusingly, Trump supporters are more suspicious of the remdesivir results than a lot of scientists. Why? It’s unclear exactly why other than that they still seem to prefer hydroxychloroquine, with Laura Ingraham still touting it even after negative studies and results suggesting that remdesivir appears promising. I can’t help but chuckle, given that, whatever its flaws, the remdesivir study is still a much better designed and carried out study than any study cited as evidence for the efficacy of hydroxychloroquine.
The consequences of bypassing EBM/SBM
As I’ve said before, bypassing SBM and EBM has consequences; Lenzer and Brownlee put it this way:
As always, it is the patient who suffers the harms of using a drug first and doing the right scientific studies later. In the case of hydroxychloroquine, potential side effects are not trivial. The drug can affect heart rhythm, potentially triggering a rare condition known as torsades de pointes, which can end in sudden cardiac death. One cardiologist posted an EKG tracing of a coronavirus patient on Twitter saying, “Long time since I’ve seen torsades-de-pointe! Careful out there! Please educate your community on the use of #Hydroxycholoroquine.” And a recent study of patients treated with chloroquine (a drug related to hydroxychloroquine and also granted emergency use approval by the FDA) found that 11 of 81 patients died—many with evidence of cardiac injury, which caused the researchers to stop part of the study before it was completed. Unfortunately, that study also did not include a placebo arm on the grounds that the researchers thought it would be “unethical” to deprive study participants access to the drug. But given that there is no idea whether the drug causes more harm than benefit, this appeal to ethics might itself be considered unethical.
A month after telling doctors that prescribing hydroxychloroquine and chloroquine was okay, on April 24 the FDA issued a new advisory suggesting that the drugs should only be prescribed to patients who are in the hospital or enrolled in a clinical trial. While this may or may not cut down on potentially dangerous prescriptions, it won’t do much to improve medical knowledge, because trials enrolling patients in the United States right now lack appropriate control arms, aren’t blinded, are underpowered, or have other serious design flaws.
When it comes to remdesivir, based on one trial and ignoring a negative trial, Dr. Fauci has declared remdesivir to be, in essence, the de facto standard of care for treating hospitalized patients with COVID-19. That premature adoption means we might never know how well it actually works or if it even does work. This pronouncement and the EUA from the FDA for remdesivir (issued Friday), mean that, from now on, studies (at least of hospitalized COVID-19 patients) can’t be carried out with a placebo control anymore because it would be considered unethical. All of these studies, going forward, will have to test standard of care (now remdesivir) against standard of care plus new experimental therapeutic.
Perhaps patients should be forgiven for continuing to grasp at unproven remedies for a frightening disease. But what about the physicians and researchers, not to mention politicians, arguing that there is no time for randomized controlled trials? Many hold up Raoult, Zelenko, the Chicago trial, and other poorly designed studies as proof that hydroxychloroquine and remdesivir work. They are, in effect, saying that it’s better to make a decision based on bad studies now than to wait for the results of properly controlled ones. But given that bad studies are as likely to be wrong as right—and probably more likely to be wrong because they typically are biased toward the result desired by the researcher or study sponsor—why bother with a study at all? Why not try anything—prayer, iridology, homeopathy? At least those are less likely than the drugs to cause dangerous side effects.
How about intercessory prayer? No, I’m serious. This news story was all over social media this weekend about a randomized clinical trial being carried out to test whether intercessory prayer results in better outcomes in COVID-19 patients. (Here’s the ClinicalTrials.gov entry, if you don’t believe me.) It’s not even recruiting yet, but NPR did a news story about it on Friday!
Although we have not seen a pandemic like this in over 100 years, some things never change. Human nature, for instance, doesn’t change, and, now as then, physicians hate feeling powerless against a disease for which they have no disease-specific therapy, leaving them supportive care alone while hoping the patient can ride out the disease and recover. The culture of medicine is very much biased to “do something, anything” with an attitude of, “What’s the harm?” when a patient is facing imminent death. As Lenzer and Brownlee argue, though, yes, some people will die waiting for properly designed and conducted randomized clinical trials, but in the end that toll is likely to be far less than if early treatment attempts are based on bad science without proper controls. Thus far, thanks to politics, social media, old media, and opportunistic snake oil salesmen, we are failing COVID-19 patients when it comes to assuring that new treatments are based on rigorous science. Sadly, it turns out that most physicians are not nearly as dedicated to science-based medicine as they would like to believe.