Asserting its independence, FDA revokes chloroquine authorizations

Agency also warns against using hydroxychloroquine or chloroquine with Gilead’s remdesivir

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FDA took more than six weeks to rescind the EUA for hydroxychloroquine and chloroquine after the agency first raised concerns over the safety of the malaria drugs to treat COVID-19. The move reverses a decision that brought the agency accusations of kowtowing to President Donald Trump, who touted the drugs’ potential to cure the disease in a March 19 press briefing.

FDA granted the drugs Emergency Use Authorization on March 28 based on anecdotal and in vitro evidence, some of which the agency walked back Monday.

The agency’s decisions on hydroxychloroquine and chloroquine for COVID-19 had become a test of FDA Commissioner Stephen Hahn’s independence from political pressure as evidence mounted of the drugs’ lack of benefit and dangerous cardiac liability (see “Hydroxychloroquine Testing Hahn’s, FDA’s Independence”).

The drugs' authorization also triggered the chain of events leading to the ouster of Rick Bright, the former director of the Biomedical Advanced Research and Development Authority (BARDA). Following his removal, Bright said in a whistleblower complaint that the EUA was issued after FDA came under extraordinary pressure from Trump, HHS Secretary Alex Azar and administration supporters to grant broad, unrestricted approval to the drugs (see “Bright Shines Harsh Light On America’s COVID-19 Preparedness, FDA’s Independence”).

FDA said Monday that it revoked the EUA after determining the drugs are “unlikely to be effective in treating COVID-19,” adding that “the known and potential benefits of CQ and HCQ no longer outweigh the known and potential risks.” It cited the potential for serious cardiac side effects.

The agency also warned that taking hydroxychloroquine or chloroquine in combination with remdesivir could reduce the antiviral activity of the therapy from Gilead Sciences Inc. (NASDAQ:GILD). Remdesivir is the only other treatment to have been authorized for COVID-19.

Reversal reasoning

FDA’s decision to revoke the EUA was based on new clinical data as well as the reevaluation of information initially used to justify the March 28 authorization of the drugs, FDA Chief Scientist Denise Hinton said in a letter to Gary Disbrow, the director of BARDA’s medical countermeasure programs. BARDA, which sponsored the EUA application, requested the authorization be revoked earlier on Monday.

The agency now believes the suggested dosing regimens are unlikely to produce an antiviral effect, Hinton wrote.

The EUA had relied on scientific publications suggesting lung concentrations of hydroxychloroquine resulting from the recommended dose were higher than the in vitro EC50 values for blocking SARS-CoV-2.

Upon revising its calculations, FDA clinical pharmacology reviewers concluded that drug levels in lung tissue resulting from the recommended dose would be too low to inhibit the virus; and that higher doses would lead to unacceptable toxicities.

FDA also cited data from a pair of trials in patients hospitalized with COVID-19 as a reason for the revocation.

In the first, published May 14 in The BMJ, a team of researchers from Chinese institutions including Shanghai Jiao Tong University and Hubei University of Medicine found hydroxychloroquine had no effect on whether SARS-CoV-2 was detectable in the respiratory tract after 28 days compared with standard of care.

The second readout, from the University of Oxford’s RECOVERY study, was reported June 4. The randomized, controlled master protocol study found that hydroxychloroquine failed to benefit hospitalized COVID-19 patients (see “Fresh Doubt on Hydroxychloroquine”).

“Only randomized controlled trials can answer the question of whether HCQ or CQ is of clinical benefit in hospitalized patients with COVID-19, and the RECOVERY Trial results offer persuasive evidence of a lack of benefit of HCQ,” Hinton wrote.

Safety concerns also tipped the scales.

FDA said that between its FAERS database and the American Association of Poison Control Centers' National Poison Data System, there were 385 reports associated with hydroxychloroquine or chloroquine use, and among those, there were 109 cases of serious cardiac adverse events.

“In light of ongoing reports of serious cardiac adverse events and several newly reported cases of methemoglobinemia in COVID-19 patients, the Agency has concluded that the known and potential benefits of CQ and HCQ do not outweigh the known and potential risks for the authorized uses,” Hinton wrote.

As of May 22, the Strategic National Stockpile had dispensed about 2.4 million seven-day treatment courses of hydroxychloroquine. BARDA had received data reports from 1,762 patients who received the drug under EUA, as of May 26.

HCQ’s rise and fall

Monday’s decision to reverse course comes more than a month after The BMJ's study, and over six weeks after FDA issued a safety warning regarding use of the two malaria treatments for COVID-19.

FDA issued the EUA nine days after a March 19 press briefing at which President Trump touted chloroquine and hydroxychloroquine as “very powerful” drugs with “very, very encouraging early results” against SARS-CoV-2, despite a lack of substantive clinical evidence. He also falsely stated that FDA had “approved” the drugs for COVID-19.

The EUA was based on “limited in-vitro and anecdotal clinical data in case series,” FDA wrote in authorizing the drugs’ use for COVID-19. Trump’s enthusiasm for the antimalarials, and the evidence supporting their safety and efficacy to treat COVID-19, have raised questions about the scientific basis for the EUA (see “FDA’s Authorization of Malaria Drugs for COVID-19 Looks Like Political Science”).

In an April 23 interview with Washington Editor Steve Usdin on the BioCentury This Week podcast, Hahn was unequivocal that he would terminate the EUA if the evidence did not hold up. In the event that trials demonstrate that hydroxychloroquine or chloroquine are not safe and effective for treating COVID-19, FDA “would absolutely use those data and we would rescind the EUA,” Hahn told BioCentury (see “FDA’s Hahn Denies Political Interference”).

A day later, FDA issued a warning cautioning against the use of the drugs for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems.

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