The FDA today repealed the emergency use authorization (EUA) it granted in March to anti-malarial drugs chloroquine phosphate and its less toxic metabolite hydroxychloroquine sulfate as treatments for COVID-19, citing a lack of consistent replication of earlier promising results and a randomized controlled clinical trial that showed no clinical benefit for hydroxychloroquine.

Hydroxychloroquine in particular became a household word in the weeks since the onset of the COVID-19 pandemic, after President Donald Trump first advocated its use in combination with azithromycin—“What do you have to lose?” he exclaimed during the April 4 Coronavirus Task Force Briefing. Last month, he disclosed that he had taken the drug to protect from infection with the SARS-CoV-2 virus.

But in a letter dated and made public today, Rear Admiral Denise M. Hinton, the FDA’s Chief Scientist, granted the Biomedical Advanced Research and Development Authority (BARDA)’s request to undo the emergency use authorization it granted March 28 to hydroxychloroquine and chloroquine at BARDA’s request.

Rear Admiral Hinton cited data from a large randomized controlled trial that showed no evidence of benefit for mortality or other outcomes such as hospital length of stay or need for mechanical ventilation of hydroxychloroquine treatment in hospitalized patients with COVID-19.

A memorandum attached to the letter cited the 11,000-plus patient, Phase II/III RECOVERY trial (NCT04381936), which assessed hydroxychloroquine among six potential treatments for COVID-19. On June 5, investigators stopped enrolling participants in the 1,542-patient hydroxychloroquine arm.

“There is no beneficial effect of hydroxychloroquine in patients hospitalized with COVID-19,” Peter Horby, MD, PhD, and Martin Landray, MB ChB, PhD, FRCP, both of the University of Oxford, concluded in a statement, adding: “The RECOVERY Trial has shown that hydroxychloroquine is not an effective treatment in patients hospitalized with COVID-19.”

In addition to hydroxychloroquine, the RECOVERY trial also evaluated azithromycin, Abbvie’s Kaletra® (Lopinavir-Ritonavir), the corticosteroid dexamethasone, convalescent plasma, and Roche/Genentech’s Actemra® (tocilizumab).

Hydroxychloroquine and chloroquine are among the approximately 100 drugs and vaccines that GEN is “Keeping an Eye On” in its COVID-19 Drug & Vaccine Candidate Tracker, which now counts nearly 250 candidates in development against the virus.

Disappointing results

The FDA letter cited another randomized clinical trial with disappointing results for hydroxychloroquine: In a study published May 14 in BMJ, Wei Tang, MD, of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, led a team of Chinese researchers that concluded: “Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate COVID-19.

The team randomized 150 patients, half to hydroxychloroquine plus standard of care, the other half to standard of care alone—defined as including the provision of intravenous fluids, supplemental oxygen, regular laboratory testing, SARS-CoV-2 testing, hemodynamic monitoring, and intensive care, as well as the ability to deliver concomitant medications. Hydroxychloroquine was administrated at a loading dose of 1200 mg daily for three days followed by a maintenance dose of 800 mg daily, for a total treatment duration of two weeks for the 148 mild-to-moderate COVID-19 patients, and three weeks for the two severe COVID-19 patients.

“Adverse events were higher in hydroxychloroquine recipients than in non-recipients,” Tang and colleagues also concluded in the study, which according to the team was the first randomized controlled trial evaluating administration of hydroxychloroquine in patients with COVID-19.

The team also took a swipe at Trump given his public advocacy for hydroxychloroquine: “Such a presidential endorsement stimulated an [sic] rapid increase in demand for hydroxychloroquine, which obscured the negative aspects of this drug.”

The FDA said the Tang study offered the highest quality data on viral RNA shedding of eight studies evaluated by the agency, since it was the largest randomized controlled trial assessing probability of negative conversion.

“No longer reasonable”

“At the time the EUA was issued, it was reasonable to assume that an impact on viral shedding would be associated with a clinical benefit for patients,” according to an FDA staff memo detailing the agency’s thinking on hydroxychloroquine and chloroquine. “However, neither a favorable impact of CQ or HCQ on viral shedding nor an established clinical benefit of a decrease in viral shedding has been borne out by data and reports available since the EUA was issued.”

Other reasons cited by Rear Admiral Hinton for the FDA’s about-face since March:

  • Earlier observations of decreased viral shedding with hydroxychloroquine or chloroquine treatment have not been consistently replicated.
  • The NIH no longer recommends use of chloroquine or hydroxychloroquine outside of a clinical trial, and current U.S. treatment guidelines do not recommend the use of either drug in hospitalized patients with COVID-19 outside of such a trial.
  • The agency no longer believes that suggested dosing regimens for hydroxychloroquine and chloroquine are likely to produce an antiviral effect.

“FDA has concluded that, based on this new information and other information discussed in the attached memorandum, it is no longer reasonable to believe that oral formulations of HCQ [hydroxychloroquine] and CQ [chloroquine] may be effective in treating COVID-19, nor is it reasonable to believe that the known and potential benefits of these products outweigh their known and potential risks,” Rear Admiral Hinton wrote to Gary L. Disbrow, PhD, BARDA’s Deputy Assistant Secretary and Director, Medical Countermeasure Programs.

VA, FDA signal retreat

Yet weeks before today’s FDA letter, the Trump administration began signaling a retreat from hydroxychloroquine when U.S. Secretary of Veterans Affairs Robert Wilkie—a Trump nominee sworn in on July 30, 2018, following U.S. Senate confirmation—told a subcommittee of the U.S. House of Representatives Committee on Appropriations that the Department of Veterans Affairs had “ratcheted down” its use of hydroxychloroquine to treat veterans with COVID-19.

Wilkie told the Subcommittee on Military Construction, Veterans Affairs, and Related Agencies on May 28 that VA providers treated three patients with hydroxychloroquine the previous week, down from the high of 404 patients the week of March 29. In total, 1,300 veterans were treated with the drug, Wilkie wrote in a letter to U.S. Senate Minority Leader Chuck Schumer (D-NY).

“People in sound mind asked to be given this experimental treatment. The other option was to do nothing,” Wilkie said. “Everyone is learning this is in real-time, and we followed FDA guidelines on this.”

The FDA on March 28 issued an emergency use authorization allowing healthcare providers to make available chloroquine phosphate or hydroxychloroquine sulfate to “patients for whom a clinical trial is not available, or participation is not feasible,” adding “FDA encourages the conduct and participation in randomized controlled clinical trials that may produce evidence concerning the effectiveness of these products in treating COVID-19.”

However, on April 24, the FDA issued an advisory to healthcare professionals cautioning against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. The agency cited reports of serious heart rhythm problems in patients with COVID-19 treated with hydroxychloroquine or chloroquine, often in combination with azithromycin and other heart medicines designed to prolong the QT interval seen in an EKG test of heart function—as well as increased use of these medicines through outpatient prescriptions.

“We will continue to investigate”

“Hydroxychloroquine and chloroquine have not been shown to be safe and effective for treating or preventing COVID-19,” the FDA said. “We will continue to investigate risks associated with the use of hydroxychloroquine and chloroquine for COVID-19 and communicate publicly when we have more information.”

Both hydroxychloroquine and chloroquine have been approved by the FDA, which said its revoking of emergency use authorization in COVID-19 did not change earlier approvals of the drugs by the agency. Hydroxychloroquine is still approved as a treatment for select indications of malaria, lupus, and rheumatoid arthritis, while some versions of chloroquine are also approved for the treatment of malaria.

Hydroxychloroquine is marketed by Sanofi in about 60 countries under the brand names Plaquenil®, Quensyl®, and Plaquinol® (hydroxychloroquine sulfate). Sanofi also markets Aralen® (chloroquine phosphate), while both drugs are made in generic versions by numerous manufacturers. Azithromycin is marketed by Pfizer as Zithromax® (azithromycin) and Zmax™ (azithromycin extended release), and in generic form by numerous manufacturers.

“FDA has determined that the drugs are safe and effective for these uses when used in accordance with their FDA-approved labeling, and patients prescribed these drugs for their approved uses should continue to take them as directed by their healthcare providers,” the FDA stated in a Frequently Asked Questions letter released by the FDA in parallel with Rear Admiral Hinton’s letter.

“There is no new information that impacts FDA’s conclusions about the safety and efficacy of CQ or HCQ for their currently approved uses.”

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