Posted on Jun 16, 2020, 2 p.m.
The FDA has revoked the EUA granted to the antimalarial drugs chloroquine phosphate and the less toxic metabolite hydroxychloroquine sulfate for treatments against COVID-19, this repeal cites a lack of consistent replication of earlier results and a randomized clinical trial that showed no benefit.
The drugs have become a popular topic of discussion after being advocated for in combination with azithromycin by the president who even disclosed taking it himself. Recently the FDA’s chief scientist Rear Admiral Denise M. Hinton in a letter granted the Biomedical Advanced Research and Development Authority’s request to repeal the EUS granted on March 28, 2020 at BARDA’s request, citing data from a large randomized controlled trial showing no evidence of benefit for mortality or other outcomes with use of hydroxychloroquine.
The letter has a memorandum attached to it citing the Phase II/III RECOVERY Trial assessing the drug among 6 potential treatments for COVID-19 involving over 11,000 patients. This trial also evaluated azithromycin, Lopinavir-Ritonavir, dexamethasone, convalescent plasma, and tocilizumab. Chloroquine and hydroxychloroquine are among around 100 drugs and vaccines that are being watched in a tracker which contains close to 250 candidates in development.
“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.”
This letter also cited another randomized clinical trial published in BMJ with less than promising results in which the researchers 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.” As well as concluding that “Adverse events were higher in hydroxychloroquine recipients than in non-recipients.” According to the researchers this study offered the highest quality data on viral DNA shedding of 8 studies evaluated by the agency as it was the largest randomized controlled trial assessing the probability of negative conversion.
According to an FDA memo regarding the reversal of the emergency use authorization:
“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. 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 that were citing on the decision include:
- Observations of the decreased viral shedding with hydroxychloroquine or chloroquine treatment have not been consistently replicated from earlier study
- 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 FDA no longer believes that the 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.
Even before this FDA repeal it appears as if the administration was already beginning to back away from hydroxychloroquine when the US Secretary of Veterans Affairs, Robert Wilkie, told a subcommittee in a letter that they are “ratcheted down” on the use of the drug to treat veterans infected with COVID-19, stating that the VA had only treated 3 patients with the drug the previous week which was down from the high of 404 patients, and in total 1,300 veterans were treated using the drug.
“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 Emergency Use Authorization was issued on March 28, 2020, allowing healthcare providers to make the drugs available to “patients for whom a clinical trial is not available, or participation is not feasible,” adding that the “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.”
On April 24, 2020 the agency issued an advisory cautioning against the use of the drugs outside of hospital or clinical settings due to the risk of heart rhythm issues, citing reports of serious problems in COVID-19 patients treated with the drugs often in combination with azithromycin and other heart medications designed to prolong the QT interval seen in an EKG test for heart functions; as well as citing an increase of the drugs being used through outpatient prescriptions.
“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.”
Although the agency is revoking the EUA for use in COVID-19 they agency is not revoking the previous approvals for hydroxychloroquine and chloroquine as treatment for select indications of lupus, rheumatoid arthritis, and malaria.
“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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