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FDA Revokes Emergency Authorization of Malarial Drugs for Treating COVID-19
By Sangeeta Chakraborty, Ph.D.
In fewer than three months, the treatment of COVID-19 with the antimalarial drugs chloroquine (CQ) and hydroxychloroquine (HCQ) has seen some major changes.
On June 15th, the USFDA revoked the emergency use authorization (EUA) of CQ and HCQ, which were both used for the treatment of COVID-19 since March 28th. The agency determined that the statutory criteria for emergency use of the drugs are no longer met.
The decision comes in light of the new evidence that shows not only are these drugs ineffective, but they can potentially injure the heart when used as COVID-19 treatment. From the ongoing investigation of the literature that has shown serious cardiac events and other potential side effects, the FDA determined that the drug’s potential benefits no longer outweigh its known and potential risks.
Emergency Use Authorization (EUA)
On March 28th, the FDA in consultation with the Biomedical Advanced Research and Development Authority (BARDA), within the U.S. Department of Health and Human Services (HHS), issued a EUA that granted the emergency use of CQ and HCQ for the treatment of COVID-19. It allowed the drugs to be distributed from the Strategic National Stockpile (SNS), to treat hospitalized COVID-19 cases when a clinical trial was unavailable, or participation in a clinical trial was not feasible.
The initial decision was based on the data available at the time of authorization that compelled the agency to believe that both drugs could be effective in treating COVID-19. However, a follow-up reassessment of the scientific evidence forced the FDA to revoke the EUA. The decision comes across as a collaborative effort between BARDA and FDA to respond to the rapidly changing public health emergency.
“Today’s request to revoke is based on new information, including clinical trial data results, that have led BARDA to conclude that this drug may not be effective to treat [Covid-19] and that the drug’s potential benefits for such use do not outweigh its known and potential risks,” FDA chief scientist Denise Hinton wrote in his letter to BARDA’s acting director Gary Disbrow.
No Science Backing for CQ or HCQ
A reassessment of the scientific evidence by the FDA clinical pharmacology reviewers found that the suggested dosing of HCQ authorized in the EUA was not enough to have any antiviral effects. Most of the literature on which this assessment was based on, reported antiviral concentrations based on drug concentrations in the cell culture media as opposed to blood plasma. FDA scientists, however, determined that the concentrations that would be needed to have an antiviral effect against SARS-CoV-2 are much higher than the dosing regimens recommended in the EUA and that this substantial increase to achieve a therapeutic antiviral effect, could lead to unwarranted toxicity.
The agency also reviewed the literature regarding the effects of CQ and HCQ on SARS-CoV-2 RNA shedding. A randomized open-label trial from Tang et.al that compared both drugs with the standard of care alone in 150 hospitalized patients, found that the proportion of COVID-19 patients shedding viral RNA was similar in both arms of the treatments. The RT-PCR based test that tracked viral RNA shedding in specimens obtained from the upper or lower respiratory tract over a period of 28 days found that the rate of disappearance of viral RNA from these samples was similar regardless of the treatment.
The final testimony against the use of these drugs came from the big UK based clinical trial—RECOVERY—that tested the effectiveness of several treatment options including HCQ in a large group of patients (~11,000) in reducing death or reducing the need for ventilation. In light of no added benefit in the reduction of either death or severity by HCQ compared with the standard of care, the chief investigators of RECOVERY trial shut down the HCQ arm of treatment mid-way through the trial.
In their letter, the agency concluded that the suggested dosing for CQ and HCQ are unlikely to achieve an antiviral effect, that decreased viral shedding seen with HCQ or CQ has not been replicated consistently, and that there has been no benefit for death or other outcomes using the drugs in hospitalized COVID-19 patients.
Arrhythmias Observed with CQ and HCQ
The FDA said case reports from the FDA Adverse Event Reporting System (FAERS) database, published medical literature and the American Association of Poison Control Centers (AAPC), National Poison Data System (NPDS) have shown serious cardiac adverse events and patient deaths.
As per the reports collected from all the above sources, that included 109 cases, QT prolongation was the most common adverse event seen for both HCQ and CQ (73%). Apart from that, a significant number (13%) of other serious heart-rhythm problems were seen too, like ventricular arrhythmia and ventricular tachycardia. Mortality happened in 23% of the cases.
These risks may increase when these medicines are combined with other medicines known to prolong the QT interval, including the antibiotic azithromycin, which is also being used in some COVID-19 patients without FDA approval for this condition.
The FDA cautioned health care professionals and patients against the use of HCQ or CQ outside of the hospital setting or a clinical trial due to the known risks of heart rhythm problems. The Agency said they will continue to investigate the risks associated with these two drugs for COVID-19 and communicate publicly as more information accumulates.
Editor: Rajaneesh K. Gopinath, Ph.D.
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