FDA, Advocacy Group Clash Over Hydroxychloroquine

August 4, 2020
Grant M. Gallagher

As the debate on hydroxychloroquine rages on, the FDA and a new advocacy group have sparred about the appropriateness of physicians prescribing the drug for COVID-19.

The US Food and Drug Administration (FDA) and a group known as America’s Frontline Doctors have made headlines in recent days, clashing over the right of physicians to prescribe the drug off-label for COVID-19 amid scientific debate on efficacy.

"Let doctors be doctors," said Alieta Eck, MD, a primary care physician from New Jersey and former congressional candidate. “We treat people off-label all the time.”

Mere months ago, hydroxychloroquine was not a controversial drug. Due to potent activity against SARS-CoV-1, many clinicians made the reasonable estimation that chloroquine may have an impact on SARS-CoV-2.

In vitro experimentation seemed to suggest the same.

Prescriptions of the drug skyrocketed when COVID-19 hit the US.

Once President Donald Trump expressed optimism about the treatment’s potential, it became a fixture of the nation’s COVID-19 debate and symbolic of far more than one’s opinion on the efficacy of an anti-malarial.

From February to March, prescriptions for hydroxychloroquine jumped by 86.2%—from 367,346 to 683,999. Prescriptions for chloroquine jumped from 2346 to 6066—an increase of 158.6%.

However, despite claims of this trend being driven purely by a politicization of science, it is worth noting that many countries that Donald Trump is not the president of also saw spikes of hydroxychloroquine prescribing.

Still, valid questions have been raised about the safety and efficacy of the drug. The American Medical Association has strongly recommended against use of the drug, including for prophylaxis, in part due to the problem of shortages in more proven treatment areas like lupus.

On efficacy, a literature review published in the European Journal of Medicinal Chemistry in late July on a variety of potential COVID-19 treatments treated the medication as an open question, merely stating that “at present there is still no clear evidence to support the effectiveness of HCQ against SARS-CoV-2 infection, which remains to be confirmed by clinical trials.”

Other clinicians, and even the US FDA, have taken stronger stances, declaring that the evidence is overwhelming. And the drug was removed from World Health Organization trials after a string of negative study results, despite contestation of some data sources.

Infectious Disease pharmacist Jason Pogue, PharmD turned to Twitter recently to present a deep dive on less contested hydroxychloroquine data, arguing that even clinicians who were optimistic about the drug have largely moved from a bullish to a bearish view.

I promise that if #hydroxychloroquine was an effective therapy for #covid19 we would tell you. Many of us (myself definitely included) were hopeful that it would be at the onset of the pandemic. We now know definitively that it doesn’t work. A (long) thread

— Jason Pogue (@jpogue1) July 30, 2020

The primary objection to hydroxychloroquine on safety grounds has revolved around the fact that the medication is known to have potential QT-prolongation impacts on the heart.

While it has been used in rheumatology care for some time and there is a plethora of data on maximizing safe use through monitoring, studies such as the May 1 JAMA Cardiology publication suggested serious QT-prolongation issues.

“Hydroxychloroquine with or without azithromycin for treatment of COVID-19 was associated with frequent QTc prolongation, and those taking hydroxychloroquine and azithromycin had greater QT prolongation than those taking hydroxychloroquine alone,” study authors wrote.

However, proponents of the drug have raised that it was used in a far different manner than they would advocate for.

"Once somebody is in the hospital, all of this stuff is already happening to them, and it’s too late for hydroxychloroquine," Eck has said. "I have no idea why they never did a randomized study of early cases before patients are sick enough to go in the hospital."

According to the JAMA authors, 33% of patients were already critically ill at the time of testing, and 26% were mechanically ventilated. If a patient is on a respirator, they are already experiencing the respiratory distress that proponents argue hydroxychloroquine could have possibly assisted in limiting.

Additionally, most patients in the study group had at least 1 cardiovascular comorbidity and were taking 2 or more QTc-prolonging medications before being prescribed hydroxychloroquine, and 51% had a high-risk baseline cumulative Tisdale score.

Results like these, along with retracted Surgisphere data, show what even some hydroxychloroquine skeptics view as an unrealistic level of harm from the drug. Headlines such as "Trump Touts Unproven Drug" have become common, as have headlines accusing regulators of suppressing the truth about the drug. Along with a wave of political battles, these mixed results have muddled the scientific debate significantly.

Groups like America’s Frontline Doctors have argued that the matter is up for individual clinical judgment. For most infectious disease specialists, it is now a bear market for hydroxychloroquine.

But for those looking to disregard the noise who are curious about outpatient prophylactic use alongside the addition of zinc and azithromycin, study results due in December 2020 are likely to be elucidating. Until then, the political battle is likely to rage on.