This story is part of The Cancer Letter’s ongoing coverage of COVID-19’s impact on oncology. A full directory of our coverage is available here.
Governments respond differently to crises which threaten the health of their citizens. For example, during the current SARS-CoV-2 pandemic, some countries instituted an immediate lockdown whilst others have not restricted social activities, or have done so too late to be maximally effective.
The question is: What prompts these different policies?
I have been involved in mitigating the health effects of several catastrophes, including the nuclear power facility accidents in Chernobyl and Fukushima-Daiichi, a radiation accident in Goiania, Brazil, and earthquakes in Armenia and Mexico City. A consistent feature of the leaders of countries where these events occurred was to seek—and mostly follow—the advice of scientific and medical experts.
This morning, in the clinic, two people asked me whether they should be taking chloroquine, which they said they could obtain on the black market for an exorbitant price. I cautioned against this.
For example, my Soviet colleagues and I met frequently with members of a special committee of the Politburo, including General Secretary Mikhail Gorbachev, immediately after the Chernobyl accident. We kept them advised of our interventions at least weekly, if not daily. When we proposed using a molecularly-cloned hematopoietic growth factor (sargramostim) to treat the most severely affected victims, they wanted to see the evidence that this posed no danger.
At that time, we had only treated monkeys exposed to high-dose ionizing radiation, but the results were encouraging. Still, the Politburo was conservative and science-based, and it was only after two of us self-administered the drug (and survived) that we were allowed to proceed.
This is not to say the Soviet government was forthcoming with details of the accident, but they acted rationally when it came to medical interventions.
My experience after the Fukushima accident was similar. Japanese colleagues and I met frequently in the Prime Minister’s Office and with Diet members to evolve a science-based strategy for evacuations, interventions, etc.
Contrast this with President Donald Trump’s promotion of chloroquine and hydroxychloroquine to treat people with COVID-19. His recommendation to Americans is based on anecdotal data of in vitro anti-SARS-CoV-2 activity from two studies in China and uncontrolled clinical trials in China and France. In the French trial, 20 subjects received hydroxychloroquine with or without azithromycin and were compared with 14 controls who declined the intervention.
The endpoint in the French study was virus clearing, an unvalidated surrogate endpoint.
Add to this lack of randomization and blinding and a few other methodological issues. In contrast, a double-blind, placebo-controlled randomized trial of more than 1,500 subjects in Singapore at risk for influenza reported no benefit, despite similar in vitro anti-influenza virus activity. Importantly, 45% of subjects in the chloroquine arm reported adverse events.
Apparently, the concept of evidence-based medicine has not reached the White House, where some members of the Trump administration also recommended prayer to stop an AIDS epidemic amongst intravenous drug abusers.
Despite these shaky data, a tweet by President Trump on 21 March declared that the combination of hydroxychloroquine and azithromycin “has a real chance to be one of the biggest game changers in the history of medicine.” (Don’t tag Lister, Jenner, Pasteur, or Fleming.)
Gadzooks! How would Trump know?
The French study is so flawed that on April 3 the International Society of Antimicrobial Chemotherapy, publisher of the Journal of Antimicrobial Agents, issued this expression of concern about the paper that convinced Trump of the efficacy of chloroquine and hydroxychloroquine:
“The ISAC Board believes the article does not meet the Society’s expected standard, especially relating to the lack of better explanations of the inclusion criteria and the triage of patients to ensure patient safety,” the statement reads. “Although ISAC recognises it is important to help the scientific community by publishing new data fast, this cannot be at the cost of reducing scientific scrutiny and best practices.”
Although many scientists, myself included, share this concern and can pile on a few others, President. Trump’s enthusiasm hasn’t been dampened. When a person of his stature promotes a therapy, the endorsement has serious consequences.
This morning, in the clinic, two people asked me whether they should be taking chloroquine, which they said they could obtain on the black market for an exorbitant price. I cautioned against this.
One could see Trump’s science advisors cringe as he continued to argue for this therapy.
Anthony Fauci, a respected scientist and infectious disease expert, tried to moderate this claim, but was restrained by the president on several occasions. Fauci, director of the National Institutes of Allergy and Infectious Diseases (NIAID), who supervised U.S. responses to epidemics such as AIDS and the 2009 influenza A(H1N1)pdm09 pandemic, serves at the will of the president, limiting what he can say—lest he be transferred to the Bethesda Post Office.
Being a smart guy, Fauci probably thinks it’s better for the nation if he stays calm than if he gets tossed out. (I agree.) God knows what he says when he gets home, poor man. His wife must be a saint.
To quote The New York Times, “Day after day, the salesman turned president has encouraged people with COVID-19 to try hydroxychloroquine with all of the enthusiasm of a real estate developer selling time shares. The passing reference he makes to the possible dangers is usually overwhelmed by the full-throated endorsement. ‘What do you have to lose?’ he asked five times on Sunday.”
President Trump isn’t alone in his enthusiasm.
His co-promoters include such scientific luminaries as Peter Navarro (his trade adviser), Dr. Mehmet Oz (a television doctor), Larry Ellison, of Oracle, Laura Ingraham and co-conspirators on Fox News, as well as Rudolph Giuliani, who has interrupted stamping out corruption in Ukraine to help stamp out the SARS-CoV-2 pandemic.
With the numbers of crises Trump creates almost daily, we’ve already forgotten about the detention of migrants, the border wall, the Russia inquiry, impeachment, scrubbing the EPA of scientists with knowledge of climate change, reducing air pollution control standards, etc. Who can keep up? The administration’s cavalier attitude toward science may ultimately cost the nation many more lives than the SARS-CoV-2 fiasco.
Recently, Trump turned a visit to the Centers for Disease Control and Prevention (CDC) into political theater by wearing a MAGA hat. One shudders to think what scientists and epidemiologists there made of this carnival.
The latest insult to common sense and the importance of leadership came at a SARS-CoV-2 briefing on Friday, April 3, when the president announced the CDC recommendation that Americans wear face masks, but emphasized that this was voluntary: “You don’t have to do it. I’m not going to do it.” It would be difficult to classify this count-me-out attitude as leadership in the tradition of FDR and Winston Churchill.
The president used his bully pulpit to speed approval of this unscientific approach through the FDA, another public service agency part of the Executive Branch. Failure to take orders could earn FDA Commissioner Stephen Hahn a position beside Fauci in the Bethesda PO, along with HHS Secretary Alex Azar. They would make a formidable team.
A randomized clinical trial of hydroxychloroquine and azithromycin in persons with COVID-19 has begun at Rutgers Cancer Institute [See related story on page]. Unfortunately, the study design, with the primary endpoint of virus load, is unlikely to provide a definitive answer to questions of safety and efficacy. There is no arm receiving placebo-only, which may reflect the misguided belief of potential subjects that they need these drugs, thanks to the president’s unfounded and unbounded enthusiasm.
Sadly, we have been down this path before, thanks to political support for “amazing cancer cures,” including shark cartilage, laetrile, coffee enemas, and vitamin C. Once such myths are created, it takes many years and many studies to eradicate them.
And let’s not forget the potential to do harm directly, because Dr. Trump’s Amazing COVID Cure has created shortages of these drugs for people with diseases where they are proven safe and effective—and has led to the poisoning (and death) of people drinking a chloroquine formulation designed to kill fish parasites.
Trump et al. are chipping away at the 267-year tradition of responsible experimentation in medicine.
In 1753, the British naval surgeon James Lind published his account of the comparative treatment of sailors with scurvy: “their cases as similar as I could have them.” He divided 12 sick sailors into six pairs, giving each pair a different dietary supplement: cider, diluted sulfuric acid, vinegar, sea water, two oranges and a lemon or a purgative.
He noted: “The most sudden and visible good effects were perceived from the use of the oranges and lemons.” So much for power calculations. (One can only wonder what an Institutional Review Board would make of the sulfuric acid cohort.)
Progress toward understanding whether therapies were effective was slow, but steady. For example, 145 years later Johannes Fibiger, a Danish physician, studied 484 persons with diphtheria, giving them a serum treatment or not based on what day they were admitted to a Copenhagen hospital.
Fibiger argued for the need “to eliminate completely the play of chance and the influence of subjective judgment,” indicating a clear understanding of the hazards of uncontrolled comparisons. Many scientists, physicians, epidemiologists and statisticians, too numerous to mention, realized the need for scientific rigor in the evaluation of the safety and efficacy of medical interventions.
In 1990, Gordon Guyatt introduced a concept he called “scientific medicine” where one would evaluate the quality of data supporting a therapy decision. The response of his colleagues was less than enthusiastic, because of the implication prior medical decisions were unscientific. Undaunted, Guyatt tried a new term: “evidence-based medicine.”
It’s difficult to believe this term first appeared in the biomedical literature in 1991, only 30 years ago. Today, evidence-based medicine is taken for granted. Evidence-based medicine is, in fact, the alternative to voodoo-based medicine.
What physician would recommend a therapy not evidence-based, except in the context of a controlled trial? All too many, it seems, given reports of physicians prescribing chloroquine and hydroxychloroquine prophylactically and therapeutically.
Apparently, the concept of evidence-based medicine has not reached the White House, where some members of the Trump administration also recommended prayer to stop an AIDS epidemic amongst intravenous drug abusers. This is not to say that every intervention needs to be proven safe and effective in a double-blind randomized placebo-controlled clinical trial. (Consider the use of parachutes when jumping out of a plane at 10,000 meters.) However, we need an organized, structured, statistically validated approach to know whether a new therapy works.
In Hamlet (Act 4; Scene 3), Claudius remarks: “Diseases desperate grown, / By desperate appliance are relieved, / Or not at all.” Certainly, the SARS-CoV-2 pandemic is a desperate disease, and we may need desperate appliances to save the lives of people with COVID-19.
However, this challenge requires a considered approach. There are many approved drugs, and we need our best scientists and physicians to carefully and quickly use modern analytical techniques to identify a hierarchy for testing. Resources are limited and time is of the essence.
How are these drugs more compelling than all the other drugs?
Testing chloroquine or hydroxychloroquine based on a hunch from someone with no scientific credentials means another, perhaps more promising, drug will not be tested.
In critical situations such as the current SARS-CoV-2 pandemic, large randomized controlled trials are not always feasible, and empirical therapy may be justified.
However, physicians need to demand careful and critical interpretation of data from such uncontrolled trials, and the trials should be structured as best possible to give definitive answers.
The human cost of the SARS-CoV-2 pandemic is considerable, but most of us will survive. However, we may not survive the politically motivated desecration of the carefully constructed 267-year-old methodology for advancing human health.
Judgments about safety and efficacy should not be made by persons lacking appropriate expertise, and certainly shouldn’t be promoted to the public. Continued study of chloroquine and hydroxychloroquine in persons with COVID-19 in the context of a clinical trial is reasonable. However, their use to prevent SARS-Cov-2-infection or prevent COVID-19 is without scientific basis.
President Trump might take a lesson from Lionel Trilling, who said: “I defeated myself long ago when I rejected the way of chutzpah and mishegass in favour of reason and diffidence.”
The human cost of the SARS-CoV-2 pandemic is considerable, but most of us will survive. However, we may not survive the politically motivated desecration of the carefully constructed 267-year-old methodology for advancing human health.
And, in these holy days of Easter and Passover, please join me in prayer for the health of Anthony Fauci.
