“Real world evidence” vs. COVID-19?

It’s been a while since I wrote anything about the use of hydroxychloroquine, but leave it to WND to give me a reason to revisit the topic. Hydroxychloroquine (HCQ), as you might recall, is an antimalarial drug that also has mild immunosuppressive properties that make it also useful to treat rheumatoid arthritis and other autoimmune diseases. Early in the COVID-19 pandemic, HCQ was portrayed as a “miracle” drug to treat COVID-19, even though the evidence supporting its use for this indication was slim to nonexistent. To some extent, I could understand trying HCQ. The early days of the pandemic were desperate times. COVID-19 was a new disease, and it was making patients very, very sick in large numbers. There were no known treatments other than supportive care, and, back then, no vaccine. A year ago, somehow HCQ seemed to find its way into pretty much every hospital’s protocol to treat COVID-19 based on anecdotal evidence. The FDA even granted it an ill-advised emergency use authorization (later rescinded). Meanwhile, the dedication to the use of this drug in many sectors became almost cult-like, and the cult continues today, as I saw in an op-ed in WND by Joel Hirschhorn entitled COVID scandal: Feds ignored 2016 law requiring use of real world evidence.

Before I get to Hirschhorn’s torturing of science and the law (not to mention “real world evidence”), let’s look at some history since last April. As we know, the use of HCQ didn’t pan out. Indeed, after initial enthusiasm, it wasn’t long before a drip-drip-drip of negative studies started eroding support for the drug as a treatment for COVID-19. Examples included a randomized controlled clinical trial of the drug as post-exposure prophylaxis that was entirely negative. This was followed by two more, first, a Spanish post-exposure prophylaxis trial that was also negative. Then there was the Recovery Trial from the UK. Then the New England Journal of Medicine published a clinical trial of 667 patients with mild-to-moderate COVID-19 randomized to receive placebo or HCQ (with and without azithromycin, the other “miracle drug” being pushed at the time by Didier Raoult), with the primary outcome being clinical status at 15 days. It was completely negative. Yet another randomized controlled trial of hydroxychloroquine was published in Clinical Infectious Diseases. It was a Spanish trial of 293 non-hospitalized patients with mild COVID-19. It was negative, too. No benefit was observed with hydroxychloroquine beyond the usual care. Basically, medicine did what medicine does as negative evidence accumulates and abandoned the drug as a treatment for COVID-19. Clinical trial evidence trumps “real world evidence.”

Unfortunately, by this time, the quacks and grifters up to and including Dr. Mehmet Oz had latched on to HCQ as the “cure” for COVID-19 that “they” don’t want you to know about, up to and including Donald Trump. Worse, like masks and “lockdowns,” HCQ had become a culture war issue, largely thanks to Donald Trump and his allies seeing the drug as a way out of the pandemic without public health measures that were harming the economy and (in his view) his chances of being re-elected. There’s a reason why in July I referred to HCQ as the Black Knight of COVID-19 treatments. No matter how many limbs you hack off of it, evidence-wise, its proponents kept insisting that it works and that it was being “suppressed.” It’s an effort that continues to this day, with the same astroturf group promoting not just HCQ but an anthelminthic drug ivermectin, which is normally used to treat parasitic roundworm infections, even though there is little or no good evidence to support the use of this drug in COVID-19 either.

This brings me back to Hirschhorn’s article, which starts out basically rewriting history:

Here is the scandal. In 2016 under the Obama administration, Congress with strong bipartisan support passed the 21st Century Cures Act. It required the Food and Drug Administration to use “Real World Evidence,” or RWE, for approval of drugs. During the Trump administration, this statute was not invoked by the White House task force under Dr. Fauci. But it should have been used early in the pandemic.

Starting a year ago, courageous front-line doctors generated RWE because they were curing COVID patients with protocols that kept patients out of hospitals. Real world data showed the effectiveness of cheap generics like hydroxychloroquine and ivermectin to cure and prevent COVID-19. Dr. Vladimir Zelenko used RWE language early on and this February, in light of over 2 million COVID deaths globally, noted: “The problem is that the medical world and governments ignored REAL WORLD EVIDENCE.”

I do so love the liberal use of all caps in an op-ed. It always persuades me.

This is a massive rewrite of history. First, you might recall that I wrote about the 21st Century Cures Act several times. Basically, I was not a huge fan, because I saw the potential for the law to turn the FDA into a puppet of the pharmaceutical industry. The first time I wrote about the 21st Century Cures Act, I thought there were some good provisions in it, such as increasing funding for the NIH, but that it had a fatal flaw—several, actually. However, those fatal flaws derived from the idea that, if we only relax the “stifling” regulations of the FDA that, if you believe proponents of the bill that’s soon to become law, the magic of the free market would unleash the creativity of private industry and academia to open the spigot and let the cures to all sorts of diseases flow. The bill didn’t go very far in 2015, but by summer 2016 it was still around, still containing the same flaws, still being pushed by the same characters. I discussed both times how the central premise of the bill, that the FDA is too strict, that its “out of control” regulations are hampering medical innovation and slowing drug approval unduly while (of course) people are dying in droves waiting for the cures that government is keeping from the people, is simply not true.

When the Senate linked the bill to the “Cancer Moonshot” initiative spearheaded by Vice President Joe Biden in the wake of his son Beau’s death from brain cancer, I knew the bill was definitely going to become law, much as I got the same sinking feeling that “right-to-try” would inevitably become law. The reason? The 21st Century Cures Act funded the “Cancer Moonshot” initiative. Ironically, the 21st Century Cures Act was arguably the last big piece of legislation passed with broad bipartisan support, and it was passed right before Donald Trump became president. As how the law mandates the use of “real world evidence,” I’ll get to that in a minute.

First, however, let me just point out that the EUA for hydroxychloroquine was based in “real world evidence,” in this case mainly anecdotal evidence and poor quality evidence from case series. If there’s an example of the widespread adoption of a drug to treat a disease based on “real world evidence” that’s more concrete than HCQ, I can’t think of one. HCQ was widely adopted all over the country (all over the world, actually) based on the thinnest of “real world evidence.” Indeed, the very “evidence” cited by Hirschhorn is a perfect example of what I’m talking about! Vladimir Zelenko’s case series that was being promoted a year ago got no better the more patients he added to it.

Indeed, even the scientific rationale for using HCQ to treat COVID-19 was pretty flimsy. Based on an observation of 80 patients full of confirmation bias, Chinese doctors in Wuhan noted that no patients with lupus erythematosis became ill with COVID-19 and hypothesized that the chloroquine or hydroxychloroquine that they were taking might be the reason. Of course, during a major outbreak of infectious disease, it is people who are immunosuppressed are the very people who most rigorously obey orders to practice social distancing and self-quarantine and thereby protect themselves from infection. Be that as it may, the Chinese doctors started using the antimalarial drugs, and anecdotal evidence of success was reported, leading China to incorporate these drugs into its recommended regimen. The World Health Organization followed suit, as did several countries, and thus was born a new de facto standard of care for COVID-19 based on, in essence, no evidence other than some in vitro evidence that the drugs inhibit replication of SARS-CoV-2, the virus that causes COVID-19, anecdotes, and incredibly weak and poorly reported clinical trial evidence.

But what is Hirschhorn talking about here? Here’s the relevant passage from the 21st Century Cures Act, “Utilizing evidence from clinical experience“:

(a) In General.—The Secretary shall establish a program to evaluate the potential use of evidence from clinical experience—

“(1) to help to support the approval of a new indication for a drug approved under section 505(b); and

“(2) to help to support or satisfy postapproval study requirements.

“(b) Evidence From Clinical Experience Defined.—In this section, the term ‘evidence from clinical experience’ means data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials, including from observational studies, registries, and therapeutic use.

Nowhere in the law is the term “real world evidence” used, actually, but “clinical experience” is close enough to the term. In any event, at the time, here’s what I wrote about it:

A homeopath would love this provision, and, I’m sure, so would drug companies. Why bother with the time, bother, and expense of those pesky clinical trials to get your drug approved for additional indications, when you can rely on clinical experiences based on therapeutic use, uncontrolled observational studies, or registries instead? If I were the CEO of a pharmaceutical company, I’d love it. Indeed, the one thing this provision most definitely does not do is to speed effective treatments to patients. Rather, it smacks of being a payoff to pharmaceutical companies.

More importantly, though, nothing in this particular law says that “real world evidence” should trump clinical trial evidence, only that it should be considered, which it most definitely was when the FDA issued an EUA for hydroxychloroquine. but to Hirschhorn, it’s all a conspiracy to suppress HCQ and ivermectin:

Other physicians and the organizations leading the cause did not invoke RWE, namely America’s Frontline Doctors, the Association of American Physicians and Surgeons, and the Front Line COVID-19 Critical Care Alliance. Nor have conservative and liberal media informed the public about the legal mandate to use RWE.

In my recent book, “Pandemic Blunder,” I used RWE to conclude that 70 to 80% of COVID deaths could have – and still can be – prevented by using the cheap and effective protocols.

This, too, was noted: “In a December 2016 article in the New England Journal of Medicine titled ‘Real World Evidence – What Is It and What Can It Tell Us?’ all twelve authors were from the FDA. A big point was that RWE would come from clinical care and home or community settings as opposed to research-intensive or academic environments. … In order to assess patient outcomes and to ensure that patients get treatment that is right for them, real-world data needs to be utilized.” Perfectly applicable for supporting use of hydroxychloroquine and ivermectin protocols.

It would be interesting to see Hirschhorn’s analysis of the “real world data” that led him to make such an amazing conclusion, but I’m not about to pay for his book in order to find out. I rather suspect that it’s probably an analysis as bad as what’s been featured on a widely cited HCQ website for many months. It’s also amusing to remind people who “America’s Frontline Doctors” are. Let’s just say that none of them appear to have been truly “frontline” doctors, and one of them, Dr. Stella Immanuel, was known for saying that  gynecological problems like cysts and endometriosis are in fact caused by people having sex in their dreams with demons and witches, leading to a large number of jokes about “demon sperm.” She also claimed that scientists were making a vaccine to to prevent people from being religious. Such is the quality of the doctors producing “real world evidence” for HCQ, a bunch of quacks from the dark underbelly of medicine.

In any event, what Hirschhorn wrote in this op-ed is very much like what, for example, acupuncturists write about their quackery. They dismiss randomized clinical trials and then cite “pragmatic” studies without placebo/sham controls as superior evidence. Indeed, take a look at this old post of mine, specifically the arguments acupuncture advocates make against randomized clinical trials, and see if they don’t sound very similar to the arguments made by Hirschhorn, before he goes even further into conspiracytown, because, don’t you know, Anthony Fauci and the CDC are all about pushing vaccines, lockdowns, and masks, not “cures” found by brave maverick doctors:

Now, we see pandemic hypocrisy because articles are appearing promoting use of COVID vaccines by invoking RWE.

Days ago, this was a headline: “Real-World Evidence Confirms Efficiency of mRNA COVID-19 Vaccines.” The article notes, “A CDC study used real-world evidence to find that both Pfizer and Moderna’s COVID-19 vaccines reduced risk of infection 90% two or more weeks after the second dose.”

Every time you see data on COVID deaths remember that most could have been prevented if the government had honored the statutory mandate to use RWE. Following the science legally means using RWE.

This is a disingenuous argument at best that is very simply refuted by pointing out one simple thing: Neither the Moderna nor the Pfizer/BioNTech mRNA COVID-19 vaccines were issued an EUA based on “real world evidence.” They were issued EUAs based on large phase 3 randomized clinical trials of their vaccines, with a total of over 70,000 participants between them. The “real world evidence” in the study cited by Hirschhorn is also only among the first of many studies planned to determine how effective the vaccines are at preventing infection by and transmission of SARS-CoV-2, the coronavirus that causes COVID-19.

Depressingly, but unfortunately not surprisingly, more than a year into the pandemic and 15 months after Chinese doctors first started trying HCQ to treat COVID-19 patients in Wuhan, HCQ is still being portrayed as the “cure” for COVID-19 that could prevent three-quarters of the deaths from the disease and would render masks, social distancing, “lockdowns,” and, of course, vaccines unnecessary but that “they” don’t want you to know about. The only difference now is that it’s been joined by ivermectin. I used to say that ivermectin was the new HCQ, but both are now equally at the heart of the conspiracy theories peddled by cranks like Joel Hirschhorn on the pages of WND.