Need for Transparency and Reliable Evidence in Emergency Use Authorizations for Coronavirus Disease 2019 (COVID-19) Therapies | Drug Development | JAMA Internal Medicine | JAMA Network
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Health Care Policy and Law
May 19, 2020

Need for Transparency and Reliable Evidence in Emergency Use Authorizations for Coronavirus Disease 2019 (COVID-19) Therapies

Author Affiliations
  • 1Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 2Yale School of Medicine, New Haven, Connecticut
  • 3Yale Law School, New Haven, Connecticut
JAMA Intern Med. 2020;180(9):1145-1146. doi:10.1001/jamainternmed.2020.2402

On March 28, 2020, the US Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for the use of hydroxychloroquine and chloroquine for certain hospitalized patients diagnosed with coronavirus disease 2019 (COVID-19).1 Hydroxychloroquine and chloroquine have long been approved for the prophylaxis and treatment of malaria, with the former also used in the treatment of systemic lupus erythematosus and rheumatoid arthritis. Although these drugs appear to inhibit coronavirus replication in vitro, at the time of the EUA, there was no reliable clinical evidence to support the use of these drugs to treat COVID-19 in patients.

An EUA is an authorization for the use of unapproved medical products or unapproved uses of approved medical products during a public health emergency. The FDA Commissioner has the authority to issue EUAs after the Secretary of Health and Human Services declares a public health emergency. The EUA can only be issued for “serious or life-threatening”2 conditions for which there are no alternative treatments available. The criteria require that “it is reasonable to believe that the product may be effective” given “the totality of scientific evidence” and that the “known and potential benefits…outweigh the known and potential risks of the product.”2

As of April 30, 2020, the FDA had issued 174 EUAs, of which 143 (82.2%) have been for diagnostic tests for disease outbreaks that have affected the US. Only 4 EUAs (2.3%) had been issued for therapeutics: separate EUAs each for oseltamivir, zanamivir, and peramivir for the treatment of the 2009 influenza A(H1N1), and an EUA for hydroxychloroquine and chloroquine (issued in the same EUA) for COVID-19.

During the influenza A(H1N1) pandemic, all patients who were diagnosed early and were tested for susceptibility to existing influenza treatments showed susceptibility to oseltamivir and zanamivir. These medicines were approved for the treatment of influenza A (of which H1N1 is a subtype). They had promising susceptibility testing and established safety profiles. Coupled with a need to treat seriously ill patients, oseltamivir (an oral formulation) and zanamivir (an inhaled formulation) were authorized under EUAs for more expansive use outside their approved indications.

Investigations of new, unapproved therapies for the treatment of influenza A(H1N1) continued given the need for an intravenous treatment for severely ill patients and increasing antiviral resistance. Peramivir emerged as a potential therapeutic with encouraging results. A phase 1 study demonstrated few safety concerns with peramivir. The FDA also evaluated 3 phase 2 and phase 3 trials of peramivir. One of these trials, a double-blind, placebo-controlled multicenter phase 2 trial,3 demonstrated a treatment benefit comparable with the effect seen with the use of oseltamivir and zanamivir in the treatment of seasonal influenza. Although trials of peramivir had not yet been conducted in patients with influenza A(H1N1), the preliminary results and demonstrated susceptibility of influenza A(H1N1) viral samples to peramivir led the FDA to issue an EUA. The fact sheet for the EUA included the clinical trial data.

In contrast, for hydroxychloroquine and chloroquine, neither the EUA documentation nor the fact sheet for clinicians cites specific trials used in FDA decision-making, rendering it difficult to ascertain the totality of scientific evidence the FDA considered.4 The primary basis for the EUA was “limited in-vitro and anecdotal clinical data in case series.”1 The outcomes from studies conducted prior to issuance of the EUA for hydroxychloroquine and chloroquine were inconclusive as to the efficacy of the drugs because the studies lacked the characteristics usually associated with high-quality trials, such as appropriate comparator groups.5 Additionally, results have been inconsistent and there is little evidence that positive in vitro results translate to effectiveness in patients.

Whether or not hydroxychloroquine and chloroquine are shown to have clinical efficacy for treating COVID-19, there is a great risk of damage from issuing an EUA based on insufficient data.6 First, the EUA facilitates uncontrolled use of the drugs, channeling patients away from clinical trials (for hydroxychloroquine, chloroquine, and other drugs being investigated), thereby slowing the process of obtaining the data necessary to determine the safety and efficacy of any drug. Patients should generally be offered medications with unknown benefits but known risks only in the context of clinical trials. It is still unknown whether these drugs are effective therapies for COVID-19, but it is well documented that both medications cause QT prolongation and may result in fatal ventricular arrhythmias, particularly if taken with other medicines that also prolong the QT interval.

Second, the issuance of the EUA also appears to have sent a signal to physicians and health care institutions. After the EUA was issued, many institutions began incorporating hydroxychloroquine into their treatment protocols for COVID-19.7 An EUA, however, is only an authorization to distribute a drug, not an approval for a particular indication. A more measured response came on April 21, 2020, when the National Institutes of Health released treatment guidelines that do not recommend for or against the use of hydroxychloroquine or chloroquine because of insufficient clinical data.8 These guidelines reiterated the lack of evidence for the efficacy of these drugs in the context of COVID-19 and raised questions about whether the widespread use of hydroxychloroquine should continue.

Third, the EUA contributed to the surge in demand for these drugs to treat COVID-19, leading to shortages. For patients who take hydroxychloroquine and chloroquine for their approved indications, drug shortages are consequential. This surge has, in part, been caused by increased outpatient use of the drugs related to COVID-19 (outside the scope of the EUA), which has been further exacerbated by misinformation regarding their efficacy.

Moreover, there were soon reports of adverse events related to treatment of COVID-19 with hydroxychloroquine and chloroquine, including arrhythmias and death. On April 24, 2020, less than a month after the issuance of the EUA, the FDA published a Drug Safety Communication citing these adverse events and cautioning against the use of these drugs outside hospital settings and clinical trials.9 This communication highlighted the dangers of prematurely issuing EUAs for drugs without conclusive benefits but with well-established risks.

An EUA can be an important regulatory option during a public health crisis, as was the case for oseltamivir, zanamivir, and peramivir. Nevertheless, in the absence of credible evidence, the FDA should remain focused on promoting the dissemination of accurate information and the conduct of well-designed, well-controlled trials to produce the evidence necessary to guide informed decisions. The agency should not prematurely issue an EUA. The FDA should also be transparent and disclose the scientific evidence it considered. Without knowing the evidence, physicians cannot confidently decide whether to use a medication.

On May 1, 2020, following the release of promising preliminary results from a clinical trial in patients with COVID-19, the FDA issued an EUA for remdesivir, an investigational antiviral medicine that is administered intravenously.10 The EUA, which was issued before detailed results from the trial had been publicly released, is for the treatment of hospitalized patients with COVID-19 who meet specific criteria.10 Although the existing data for remdesivir appear to be more compelling than the data used to support the EUA for hydroxychloroquine and chloroquine, details of the trials that supported the EUA remained unavailable for at least the first 2 weeks after the EUA was issued.

As the COVID-19 pandemic continues, the public, government officials, and the pharmaceutical industry may pressure the FDA to issue additional EUAs for therapeutics. Instead of succumbing to these pressures, the agency should ensure that EUAs are only issued when they are supported by sufficient scientific evidence, and all of that evidence should be made publicly available at the time of issuance.

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Article Information

Corresponding Author: Aaron S. Kesselheim, MD, JD, MPH, Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 1620 Tremont St, Ste 3030, Boston, MA 02120 (akesselheim@partners.org).

Published Online: May 19, 2020. doi:10.1001/jamainternmed.2020.2402

Conflict of Interest Disclosures: Dr Kesselheim reported grants from Arnold Ventures and from the Harvard–MIT Center for Regulatory Science. No other disclosures were reported.

References
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US Food and Drug Administration. FDA drug safety communication: FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. Published April 24, 2020. Accessed April 25, 2020. https://www.fda.gov/media/137250/download
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