In a letter dated March 28, FDA announced it was issuing an Emergency Use Authorization for oral formulations of chloroquine phosphate and hydroxychloroquine sulfate for the treatment of COVID-19.
Read FDA announcement here.
The drugs are to be limited to those supplied from the Strategic National Stockpile (SNS) to public health authorities, and must be administered by licensed healthcare providers pursuant to valid prescriptions from licensed practitioners. The EUA also sets forth specific labeling requirements, recordkeeping, and adverse event and other reporting requirements.
Neither drug is actually approved by FDA for the treatment of COVID-19. Although it has approved some versions of chloroquine phosphate for treatment of certain strains of malaria and extraintestinal amebiasis, FDA has not approved the version of the drug held in the SNS. It has approved several versions of hydroxychloroquine for treatment of lupus and rheumatoid arthritis as well as malaria. Safety profiles for these drugs have only been developed for these approved indications, not COVID-19. However, several other countries already recommend the use of these two drugs to treat COVID-19 based on limited data from in vitro studies and case reports. While FDA would clearly prefer that their efficacy be evaluated in randomized and controlled clinical trials, it is allowing their use under an EUA in order to treat patients who would not be able to participate in such trials.
In issuing the EUA, FDA has concluded, after reviewing all available scientific evidence, that the known and potential benefits of treating COVID-19 patients with these two drugs outweigh the known and potential risks, especially since no approved alternative is currently available. Use will be limited to those adults and adolescents weighing at least 110 lbs who would not be able to participate in a clinical trial. Separate fact sheets for each drug must be provided to both healthcare providers and patients. Unless FDA authorizes extensions, all drug products must be distributed for use within their labeled expiration dates. Public health authorities must have processes in place for monitoring and reporting to FDA all related adverse events and medication errors. They must also maintain drug dispensing records and associated patient information.
There have been recent reports in the press concerning sudden shortages of these drugs, especially hydroxychloroquine (HCQ), which is required on a long-term basis by patients suffering from lupus or rheumatoid arthritis, and the shortages have been accompanied by equally sudden price increases. Simultaneously, there have been reports of hoarding, of large-quantity prescriptions written by physicians for themselves and for family members, and of prescriptions written by dentists or by specialists such as ophthalmologists for whom such prescription-writing would be highly unusual. This may indicate an intention to use the drugs prophylactically; in the case of chloroquine (CQ) in particular, pharmacological experts believe this may be ill-advised due to its potential adverse side-effects. The release of significant quantities of the drugs from the SNS should help reduce these artificial shortages and price increases for patients who need the drugs on an on-going basis. In an update published on March 31, FDA said that it was actively engaged in working with manufacturers to address the shortages, and noted that the release of drugs from the SNS amounted to 30,000,000 doses of hydroxychloroquine sulfate and 1,000,000 doses of chloroquine.
At present, the scientific evidence for the utility of CQ and HCQ in the treatment of COVID-19 is controversial. Both have been shown to have antiviral properties in vitro against a number of viruses, but more often than not efficacy in vitro does not translate into corresponding efficacy in laboratory animals or in human trials. However, in a study published in the Nature journal Cell Research in early February, Wang et al., working mostly at the Wuhan Institute of Virology, tested a group of five FDA-approved drugs and two other antiviral agents against SARS-CoV-2 (the novel coronavirus) in vitro, and reported that CQ was highly effective, as was Gilead’s antiviral remdesivir. The same group has since reported that HCQ also showed an antiviral effect, although less potent than that of CQ; however, HCQ is also significantly less toxic than CQ (Liu et al., March 2020).
The Wang et al. paper appears to have ignited a great deal of interest in CQ, particularly in China, for the potential treatment of COVID-19, since it is both inexpensive and readily available. As a result, over 20 papers on the use of CQ or HCQ for this purpose have been published in final or pre-print form during this past March, many of them referring to the 15-20 or more seemingly uncoordinated clinical trials that have been undertaken in China. An early March letter to the Japanese journal BioScience Trends written by Gao et al. from Qingdao in China, and somewhat prematurely titled “Breakthrough,” appears to be the first to discuss these trials. The authors noted that the trials had been quickly conducted to test the efficacy and safety of CQ or HCQ in the treatment of COVID-19 associated pneumonia in more than 10 hospitals around China, and stated:
Thus far, results from more than 100 patients have demonstrated that chloroquine phosphate is superior to the control treatment in inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus-negative conversion, and shortening the disease course according to the news briefing. Severe adverse reactions to chloroquine phosphate were not noted in the aforementioned patients.(Emphasis added.)
The underlying basis for this conclusion, however, is not clear. On its face, there appears to have been no peer-reviewed, published paper or even data, but simply a news briefing. Subsequent publications have reacted somewhat cautiously to this announcement. For example, Touret and Lamballerie from France, reported March 5 in Antiviral Research, observed that that:
Results were produced in ten different hospitals and possibly from a number of different clinical protocols among those listed above, which include various designs for control groups (none, different antivirals, placebo, etc.) and various outcome primary indicators. The final interpretation is therefore technically demanding, and in the absence of published data, it is difficult to reach any firm conclusion. It will be of the utmost importance to know if the observed efficacy is associated specifically with chloroquine phosphate, or if this includes… hydroxychloroquine.
In a very recent letter to the journal Clinical Infectious Diseases, Guastalegname and Vallone noted that CQ/HCQ, which have anti-inflammatory properties, may act against the later stages of COVID-19 by inhibiting the production of pro-inflammatory cytokines “and consequently blocking the subsequent cascade of events which lead to ARDS [Acute Respiratory Distress Syndrome].” They warn, however, that since the pathogenesis of COVID-19 is still unknown, the immune effect provoked by the administration of CQ/HCQ to COVID-19 patients is unpredictable. Touret and Lamballerie (above) also warn against potential toxicity, especially of CQ, since “the margin between the therapeutic and toxic dose is narrow and chloroquine poisoning has been associated with cardiovascular disorders that can be life-threatening.” Self-treatment is not recommended.
As a result of the lack of hard data and the potential for toxic effects, many of the papers published in the past month stress the urgent need for randomized, controlled clinical trials to demonstrate both the safety and efficacy of CQ and HCQ and their optimal dosing regimen if they do prove to be safe and efficacious. The release of substantial quantities of these drug products from the SNS will immediately facilitate their use in US-based clinical trials in addition to treating individual hospitalized patients.
In the March 31 update noted above, FDA announced a new policy that accords significantly increased flexibility to expanded access to not only CQ and HCQ but other treatments (including remdesivir) not currently approved for the treatment of COVID-19. This new policy, designated the Coronavirus Treatment Acceleration Program (CTAP), will be discussed in our next Alert.