As SARS-CoV-2 accelerated its worldwide spread in March, a medication with World War II roots captured the spotlight of the COVID-19 pandemic. Hydroxychloroquine—a malaria drug with anti-inflammatory properties—rapidly emerged as the de facto COVID-19 therapy, despite an exceedingly thin evidence base to justify its use. Bolstered by a rare Emergency Use Authorization from the U.S. Food and Drug Administration and widely touted by high-level political and media figures, hydroxychloroquine prescriptions skyrocketed overnight, including an astounding 46-fold spike in U.S. prescriptions after a March 19 press conference in which President Donald Trump encouraged its use.
The science backing hydroxychloroquine as a COVID-19 therapy was meager, largely restricted to a single-arm, unblinded, and nonrandomized study of 36 patients. Nonetheless, hydroxychloroquine quickly found a home as a primary COVID-19 therapeutic, with federal agencies and front-line providers adopting a stance with echoes of pandemics past: How could it hurt?
History has repeatedly answered this question: Using drugs like this can, indeed, hurt. In fact, our medical past is littered with pharmaceutical mishaps and counterproductive responses during global pandemics. The evidence is clear that prematurely electing one untested drug can cause much more harm than good.
Our modern pharmaceutical regulatory structure is built upon the skeletons of medicine’s past mistakes. History has repeatedly demonstrated that widespread use of medications without adequate evidence often results in unforeseen, harmful consequences. A roster of onetime blockbuster medications now lives on in infamy: thalidomide, a morning sickness medication marketed to European women subsequently found to have caused thousands of horrific birth defects; fenfluramine, a popular weight loss medication prescribed to millions, eventually pulled from the market and subject to a $3.75 billion settlement for causing valvular heart disease; Vioxx, a massively distributed pain reliever that subsequently notched more than 55,000 alleged deaths from heart attack and stroke.
These painful episodes are seared into physicians’ and scientists’ collective consciousness, passed from generation to generation as a reminder to exercise caution when considering new drugs or prescribing old medications for new indications. Even across a range of otherwise successful or relatively benign medications, “off-label prescribing”—the use of medications in conditions for which they weren’t approved—is associated with significantly higher rates of adverse events.
History is even more instructive when we focus on our past responses to pandemics. Here, too, we see the consequences of medications prematurely rushed to the front lines—interventions heroic in their intentions but often disastrous in their outcomes.
Pandemic responses are marked by a sense of desperation, not only among the public but also among physicians who are looking for something—anything—to save lives. This impulse can lead physicians to abandon caution and engage in widespread off-label repurposing of old medications. The 2003 SARS coronavirus epidemic—a modern historical analogue of our present-day pandemic—similarly featured rapid, sweeping use of repurposed medications before evidence of their efficacy was known. As case counts began to climb, physicians began treating patients with a combination of steroids and high-dose ribavirin—a medication that had the reputation of being a relatively broad antiviral agent. The few available studies on the impact of the drug on the SARS coronavirus were small and poorly constructed. Despite thin evidence and a list of serious side effects, including anemia, electrolyte derangements, and liver damage, the medication was quickly and widely prescribed in Hong Kong, China, Singapore, and Toronto.
Unfortunately, not only did the steroid and ribavirin combination fail as therapy, it might have worsened some patients’ outcomes. Yet even as negative evidence emerged, some providers continued to prescribe the cocktail because they wanted to do something. This was not the only instance of a failed off-label therapy during this pandemic; an exhaustive examination of the many attempted therapies during the SARS outbreak suggests that most provided little benefit and some may have even been harmful. Despite this evidence, we saw a similar response to the Middle East respiratory syndrome, or MERS, in 2011. Again, physicians tried ribavirin and even interferon—a medicine known to have a substantial toxic profile—with the hope of doing something. The response to MERS was also a reminder that drugs that work in test tubes—such as mycophenolate, a powerful immunosuppressant—can make things worse in living beings, as mycophenolate actually increased the number of MERS viral particles when tested in primates.
Finally, our most recent pandemic—the 2014–16 Ebola virus outbreak—showed us that medication mishaps during pandemics are not only a matter of poorly repurposed old drugs; the success of new medications is also notoriously difficult to predict. As Ebola spread, highly touted novel therapeutics like ZMapp—a triple monoclonal antibody cocktail—showed initial promise in primate studies but were ineffective once subjected to a randomized controlled trial. Remdesivir—an antiviral now under investigation for COVID-19—showed initial promise against Ebola in primates and was rapidly advanced to clinical trials, but ultimately proved far inferior to two later immunotherapies.
Of course, the current outbreak is much broader than SARS, MERS, or Ebola, and has already killed many more people. Doesn’t this justify more risk taking? Even the great influenza pandemic of 1918 has a lesson for us. Physicians at the time, seeking to provide relief to their patients with their available medical armamentarium, prescribed large doses of salicylates, up to 31 grams per day, which would later turn out to be toxic. Even the U.S. surgeon general recommended prescribing salicylates right before the October 1918 death spike. Research suggests that a meaningful proportion of the deaths from the great influenza pandemic may have been from the effects of this treatment rather than the disease itself.
These and similar lessons have been widely taught in schools of medicine and public health across the world. They have even found their way into the bylaws of the American Medical Association, whose code of ethics explicitly states that off-label medication usage in a pandemic should occur only “on the basis of sound scientific evidence and appropriate clinical expertise.” Nonetheless, as we have again recently seen, these lessons of history are all too easily cast aside. In times of crisis, past becomes prologue.
Shifting back to the present, hydroxychloroquine’s star has dimmed amid recent disappointing clinical trial data and mounting evidence of heart and liver toxicities. Might another repurposed drug emerge as a useful COVID-19 therapy? Of course. Even as we write, the spotlight has abruptly shifted once again to shine brightly on remdesivir, with directionally promising—albeit limited—initial trial data again racing across headlines worldwide. If eligible, patients can be enrolled in remdesivir clinical trials for moderate or severe cases of COVID-19. Outside of clinical trials, remdesivir is available in limited supply via Emergency Use Authorization. Will it work? Luckily, we have a robust scientific method at our disposal to sort out just such a question, burnished with centuries of trials, errors, and lessons.
The last great pandemic was a century ago, when the average life expectancy was nearly 30 years shorter. Humanity has made important progress since then, largely by relying on science to develop and implement public health measures, identify new therapies, and vanquish old diseases. An unprecedented unified worldwide scientific effort is now underway to study and fight COVID-19. In unsettling times like this, it is more important than ever that we recommit to the scientific method that has given us this progress. Working quickly and efficiently, we can reduce deaths and alleviate suffering, without further harming the sick—as long as we remember the lessons we’ve learned, instead of having to learn them again.
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