The FDA has determined chloroquine and hydroxychloroquine are not effective at treating novel coronavirus and revoked its earlier emergency use authorization (EUA) for the drugs to be used in COVID-19 patients. Getty Images
June 15, 2020 — The U.S. Food and Drug Administration (FDA) today revoked the emergency use authorization (EUA) that allowed use of the drugs to treat hospitalized COVID-19 (SARS-CoV-2) patients because there is no evidence showing it helps patients, while at the same time there has been a large increase in adverse event reports, including patient deaths, due to these drugs.
“We’ve made clear throughout the public health emergency that our actions will be guided by science and that our decisions may evolve as we learn more about the SARS-CoV-2 virus, review the latest data, and consider the balance of risks versus benefits of treatments for COVID-19,” said FDA Deputy Commissioner for Medical and Scientific Affairs Anand Shah, M.D. “The FDA always underpins its decision-making with the most trustworthy, high-quality, up-to-date evidence available. We will continue to examine all of the emergency use authorizations the FDA has issued and make changes, as appropriate, based on emerging evidence.”
The EUA issued in March 2020 allowed for chloroquine phosphate and hydroxychloroquine sulfate donated to the Strategic National Stockpile to be used to treat hospitalized COVID-19 patients when a clinical trial was unavailable, or participation in a clinical trial was not feasible.
The FDA determined that the legal criteria for issuing an EUA are no longer met. Based on its ongoing analysis of the EUA and emerging scientific data, the FDA determined that chloroquine and hydroxychloroquine are unlikely to be effective in treating COVID-19 for the authorized uses in the EUA. Additionally, ongoing serious cardiac adverse events and other potential serious side effects of chloroquine and hydroxychloroquine no longer outweigh the known and potential risks for the authorized use, the FDA said.
The agency said this is the statutory standard for issuance of an EUA. The Biomedical Advanced Research and Development Authority (BARDA) within the U.S. Department of Health and Human Services (HHS) originally requested the EUA covering chloroquine and hydroxychloroquine, and the FDA granted the EUA on March 28, 2020, based on the science and data available at the time.[1-6] Today, in consultation with the FDA, BARDA sent a letter to the FDA requesting revocation of the EUA based on up to date science and data.
Efficacy of Hydroxychloroquine Shows No Benefit in Treating COVID-19
The FDA said hydroxychloroquine is not effective in treating COVID-19, based on its review of data to date. The agency has a responsibility to regularly review the appropriateness of an EUA, and as such, the agency will review emerging information associated with the emergency uses for the authorized products. Recent results from a large randomized clinical trial in hospitalized patients, a population similar to the population for which chloroquine (CQ) and hydroxychloroquine (HCQ) were authorized for emergency use, demonstrated that hydroxychloroquine showed no benefit on mortality or in speeding recovery. This outcome was consistent with other new data, including data showing that the suggested dosing regimens for chloroquine and HCQ are unlikely to kill or inhibit the virus that causes COVID-19. The totality of scientific evidence currently available indicate a lack of benefit.
“While additional clinical trials continue to evaluate the potential benefit of these drugs in treating or preventing COVID-19, we determined the emergency use authorization was no longer appropriate. This action was taken following a rigorous assessment by scientists in our Center for Drug Evaluation and Research,” said Patrizia Cavazzoni, M.D., acting director of the FDA’s Center for Drug Evaluation. “We remain committed to using every tool at our disposal in collaboration with innovators and researchers to provide sick patients timely access to appropriate new therapies. Our decisions will always be based on objective and rigorous evaluation of the scientific data. This will never change.”
Hydroxychloroquine Cleared Uses
Chloroquine and hydroxychloroquine are both FDA-approved to treat or prevent malaria. HCQ is also approved to treat autoimmune conditions such as chronic discoid lupus erythematosus, systemic lupus erythematosus in adults and rheumatoid arthritis. Both drugs have been prescribed for years to help patients with these debilitating, or even deadly, diseases, and FDA has determined that these drugs are safe and effective when used for these diseases in accordance with their FDA-approved labeling. FDA-approved products may be prescribed by physicians for off-label uses if they determine it is appropriate for treating their patients, including during COVID.
Known Issues With QT-prolongation Seen in Large Numbers of Adverse Event Reports
The FDA said both hydroxychloroquine and chloroquine have similar adverse effects such as QT prolongation. However, it has been used safely for years in lupus and rheumatoid arthritis, so for the purposes of the emergency use authorization in COVID patients, it was reasonable to assume that safety data would be applicable to COVID-19 patients.
FDA clinical pharmacology reviewers have re-assessed the publications relied upon at the time of EUA authorization at the dosage suggested in the EUA. The FDA clinical pharmacology reviewers found limitations with these studies, mainly that the antiviral values reported in the literature were extracellular drug concentrations present in cell culture media and not drug concentrations in the blood plasma. The FDA recalculated the concentrations that would be needed to have an antiviral effect against SARS-CoV-2 and found they would not likely be achievable with the dosing regimens recommended in the EUA. The substantial increase in dosing that would be needed to increase the likelihood of an antiviral effect would not be acceptable due to toxicity concerns, the FDA concluded. Indeed, much higher doses of the drugs were used in many patients to try to reach therapeutic, antiviral levels.
The FDA issued a Drug Safety Communication April 23, 2020, reminding doctors there are serious side effects when using hydroxychloroquine and chloroquine in the off-label use to treat COVID-19 patients. This includes potentially life-threatening heart rhythm problems. The FDA said case reports from the FDA Adverse Event Reporting System database, published medical literature and the American Association of Poison Control Centers National Poison Data System are reporting serious heart-related adverse events and patient deaths. Read more about this alert.
Although many published papers predicted adequate antiviral effect, the majority of these papers refer to the methods and findings of the publication with the limitations noted by the FDA. In addition, conclusions in the most recent publication regarding in vitro activity of HCQ and achievable concentrations at the site of action are consistent with the FDA assessment. Results of analyses made available since the EUA was issued lead to the conclusion that it is unlikely that the dosing regimens in the EUA would be able to have an antiviral effect.
Used in lower doses hydroxychloroquine has been shown to be safe for its indicated uses. However, in much higher concentrations, combined with other QT-prolonging drugs like azithromycin, and the combination of COVID-induced myocarditis which also can cause QT-prolongation, it can create the perfect storm to cause severe, life-threatening arrhythmias, explained Andrew D. Krahn, M.D., FHRS, head of the division of cardiology at St. Paul’s Hospital, and professor of medicine at the University of British Columbia, and vice president of the Heart Rhythm Society (HRS). He is an expert in long QT syndrome (LQTS).
"All treatments have some potential downside, and both hydroxychloroquine and azithromycin are drugs we tell people not to take all the time in my business. But, in desperate times, people will take measures they feel are necessary to help patients," Krahn said. He said low potassium levels in patients might also combine to cause severe arrhythmias.
Watch an interview with Krahn in the VIDEO: Why QT-prolongation Occurs in COVID-19 Patients on Hydroxychloroquine and Azithromycin.
Medical Literature Does Not Support Hydroxychloroquine as a COVID-19 Treatment
The FDA said it reviewed the published literature available since the EUA was issued regarding the effects of CQ or HCQ on viral COVID-19 RNA shedding.[9-16] The highest quality data are those published by Tang et al. from a randomized open-label trial comparing hydroxychloroquine with standard-of-care alone in 150 hospitalized patients with COVID-19. The proportion with conversion of RT-PCR specimens obtained from the upper or lower respiratory tract to negative by day 28 was similar in both groups at multiple timepoints. Other published studies, which include an extremely small randomized trial as well as several observational comparisons, were inconsistent with respect to reporting a difference in viral RNA shedding comparing HCQ- or CQ-treated patients with others who were not treated with either of these medications.
FDA reviewers also evaluated a large observational study of HCQ and CQ with or without a macrolide antibiotics for the treatment of COVID-19 patients, based on data from a multinational registry published in the Lancet by Mehra et al. However, this publication was subsequently withdrawn by the authors because of not being able to supply data and it was not included in this agency review.
Some Hospitals Say Hydroxychloroquine Has Helped COVID-19 Patients
The initial studies the FDA based its EUA on showed the drugs may help COVID patients and some centers using the drugs say they have helped. Henry Ford Hospital in Detroit has used hydroxychloroquine as a front-line COVID treatment and found it has improved the health of many SARS-CoV-2 patients.
"Hydroxychloroquine has been used as a treatment for hospitalized Henry Ford Health System patients in accordance with the EAU guidelines, along with multiple other medications in our experience with COVID-19 since early March," said Steven Kalkanis, M.D., chief executive officer of the Henry Ford Medical Group and senior vice president and chief academic officer. "We have analyzed our data and have seen a significantly improved outcome in a group of COVID-19 patients who received hydroxychloroquine. These data are currently under review for publication in a peer reviewed scientific journal and will be shared as soon as this is completed. However, due to today’s FDA action, we have suspended the use of hydroxychloroquine outside of a clinical trial."
Henry Ford has been one of the major COVID-19 treatment centers in Detroit. With cardiac clinical trials grinding to a halt in March as the hospital postponed all nonessential procedures due to the pandemic, the cardiology department's researchers were switching over to conducting COVID-19 research and helping coordinate trials being run jointly with four other Detroit area hospital systems. The biggest is the WHIP COVID-19 study, which is testing if HQC taken as a prophylaxis can help prevent COVID infections. The study plans to enroll 3,000 healthcare workers, first responders and city transit system bus drivers who are exposed to the virus on a daily basis.
"The ongoing WHIP COVID-19 study is an FDA-approved study looking at hydroxychloroquine as a potential preventative medication for healthy, pre-screened individuals. It is not affected by the FDA’s decision today, and there is no evidence that the use of hydroxychloroquine as a potential prophylaxis presents a health risk in that setting," Kalkanis said, noting the FDA revoking the EUA only effects in-hospital use of HQC outside of clinical trials.
Read more on the WHIP COVID study, First Large-scale U.S. Study on Hydroxychloroquine COVID-19 Prophylaxis Begins in Detroit
VIDEO: Cardiologists Manage Trial Testing if Hydroxychloroquine Protects Clinicians From COVID-19 — Interview with William O'Neill, M.D.
Cardiology Societies Warned Hydroxychloroquine Would Cause Increase in Severe Arrhythmias
When hydroxychloroquine and the antibiotic azithromycin started being used as a front line treatment for COVID-19, several cardiology societies issued a joint warning statement that these drugs would have serious implications for patients with existing cardiovascular disease. Complications include severe electrical irregularities in the heart such as arrhythmia, polymorphic ventricular tachycardia (including Torsade de Pointes) and long QT syndrome, and increased risk of sudden death. The effect on QT or arrhythmia of these two medications combined has not been studied.
Related Hydroxychloroquine Content:
VIDEO: Why QT-prolongation Occurs in COVID-19 Patients on Hydroxychloroquine and Azithromycin — Interview with Andrew D. Krahn, M.D.,
VIDEO: Overview of Hydroxychloroquine and FDA Warning in its use to Treat COVID-19 — Interview with Marianne Pop, Pharm.D.
VIDEO: Cardiologists Manage Trial Testing if Hydroxychloroquine Protects Clinicians From COVID-19 — Interview with William O'Neill, M.D.
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7. Office of Clinical Pharmacology Consult Review, EUA 039, Submitted May 15, 2020.
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17. Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis [published online ahead of print, 2020 May 22] 6
18. Mandeep R Mehra, Frank Ruschitzka, Amit N Patel. Retraction—Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis The Lancet Published: June 5, 2020 Available at: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31324-6/fulltext