Emergency Use Authorization of remdesivir by the US Food and Drug Administration

May 6, 2020

Jeffrey K Aronson, Robin E Ferner*, David Nunan

On behalf of the Oxford COVID-19 Evidence Service Team
Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences
University of Oxford
*University of Birmingham

Correspondence to jeffrey.aronson@phc.ox.ac.uk

On 1 May the US Food and Drug Administration (FDA) announced that it had issued Emergency Use Authorization (EUA) for the use of remdesivir in treating COVID-19. Here is the announcement, as posted on the FDA’s website:

“On May 1, 2020, FDA issued an EUA to allow remdesivir to be distributed and used by licensed health care providers to treat adults and children hospitalized with severe COVID-19. Severe COVID-19 is defined as patients with an oxygen saturation (SpO2) ≤ 94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO), a heart-lung bypass machine. The EUA requires that fact sheets that provide important information about using remdesivir in treating COVID-19 be made available to health care providers and patients.”​

What is remdesivir?
Remdesivir (GS-5734) is a prodrug of an RNA nucleotide. Its active analogue enters and accumulates in cells, where it is converted to an active triphosphorylated metabolite. Intracellularly it inhibits viral RNA-dependent RNA polymerase, which should stop viral replication. Coronaviruses have a “proofreading” enzyme (exoribonuclease) that corrects errors in the RNA sequence, potentially limiting the effects of RNA polymerase inhibitors, but remdesivir may be able to evade this proofreading. In the laboratory, viral mutation can lead to resistance to remdesivir, but the mutant viruses are less infective.

What is the evidence of clinical efficacy so far?
Short-term outcomes have been reported for 53 of 61 patients with COVID-19 treated in over 20 different hospitals on three continents, as part of a compassionate-use (so-called “expanded access”) programme organized by the manufacturer, and not as part of a clinical trial. Thirty were being ventilated and four treated with extracorporeal membrane oxygenation (ECMO) at the start of remdesivir treatment. After a median of 18 days, 25/53 patients (47%) had been discharged from hospital and 7/53 (13%) had died. Mortality was 5% among patients who were not ventilated. The overall probability of improvement by 18 days was 68% (95% confidence interval 40–80%). Sixty percent (32/53) of patients had one or more adverse event, which were serious in 23% (12/53). The most common adverse events were abnormal liver function, diarrhoea, rashes, renal impairment, and hypotension. As the authors stated, “Interpretation of the results of this study is limited by the small size of the cohort, the relatively short duration of follow-up, potential missing data owing to the nature of the program, the lack of information on eight of the patients initially treated, and the lack of a randomized control group.”

Now the results of a Chinese double-blind randomized multicentre trial of remdesivir at ten hospitals in Hubei Province in patients with severe COVID-19 have been published, after publication of a protocol on 6 February (NCT04257656). In 237 patients, 158 of whom were given intravenous remdesivir 200 mg on day 1 and 100 mg/day thereafter for 10 days and 79 of whom were given placebo there was no statistically significant change in the time to clinical improvement: median 21 (IQR 13-28) versus 23 (IQR 15-28) days. There was no difference in the rate of adverse events (66% versus 64% of patients); remdesivir was withdrawn early because of adverse events in 18 patients (12%) versus four patients (5%) in whom placebo was withdrawn early (not statistically significant). Although an effect on viral load would have been expected, in view of the mechanism of action of remdesivir, that was not seen. This trial, whose authors originally planned to enrol 453 patients, was terminated early on 15 April because of lack of subjects when the epidemic came under control in Hubei Province.

On 5 February the same investigators logged a protocol for another similar trial, intending to enrol 308 patients with mild or moderate disease (NCT04252664); this trial was suspended on 15 April and no data have been published.

Since then, incomplete and unreviewed data from other studies have been released into the public domain. Most recently (30 April), Anthony Fauci made public some conclusions about a trial being run by the National Institute of Allergy and Infectious Diseases (NIAID), without providing the methods or data on which the conclusions were based, saying that he had an ethical obligation to reveal that remdesivir appeared to shorten recovery times, so that patients currently taking a placebo could have access to it. Since the full results of this trial have not been published, even as a preprint, this is most unusual and unhelpful for physicians trying to make decisions on behalf of their patients.

How is emergency use authorization obtained?
The processes whereby emergency use authorization is obtained are detailed in the Appendix.

What does this mean in practice?
The FDA’s decision does not mean that the manufacturers have been given permission to market the product, merely that hospital doctors will be able to obtain and use it in a stated dosage regimen for patients with known or suspected severe COVID-19 who are ill enough to require supplementary oxygen or mechanical ventilation or extracorporeal membrane oxygenation (ECMO).

Comment
In its guidance document the FDA makes several recommendations about the kind of information that drug companies should submit when applying for Emergency Use Authorization (see the Appendix). All of the FDA’s recommendations are labelled “nonbinding”, and without knowing the extent and quality of the information that has been supplied to the FDA under these regulations it is impossible to comment on whether it was justified in issuing the Emergency Use Authorization.​

In a pandemic it is desirable to have treatments assessed quickly, but clinicians need to know how best to treat their patients. Although the FDA has granted emergency approval for remdesivir, we still do not know if it is effective. The evidence that we have so far seen suggests that if remdesivir is effective its effects are small. It may shorten the duration of the illness in people with severe disease, which would be welcome and could be cost-effective, assuming that the benefits outweigh the harms. However, the most important clinical question is whether remdesivir reduces overall mortality, and we have seen no data to demonstrate that it does.

It is possible that there is additional evidence not yet in the public domain, but without seeing that evidence it is hard to comment. What we have been told is that the NIAID study showed slight benefit in time to recovery, but we still haven’t seen full details of the data, including – for example – whether the control and treatment groups were well matched. We also don’t know whether the results fit with those of the earlier smaller Chinese trial, in which the difference between treatments was much less obvious.

Expedited reviews or expedited publication are welcome. They are especially important when they show that an intervention improves important clinical outcomes. However, standards of evidence must be kept high. Hinting at positive results can lead to confusion, and arguably benefit shareholders more than patients. The manufacturers, Gilead, have announced that they will give away 1.5 million doses of remdesivir, but clinicians still do not know if remdesivir would be the right treatment choice for their patients. Even if it were, they do not know when it would be best administered.

​Footnote: On 28 March 2020, the FDA issued EUAs to allow both hydroxychloroquine sulfate and chloroquine phosphate products, donated to the Strategic National Stockpile (SNS), to be distributed “to treat adults and adolescents who weigh 50 kg or more and are hospitalized with COVID-19 for whom a clinical trial is not available, or participation is not feasible.” The evidence that these drugs are effective in COVID-19 is negligible, and there is evidence that they may have an unfavourable benefit to harm balance.

Note added on 16 June: On 15 June the FDA revoked the emergency use authorization (EUA) that allowed chloroquine phosphate and hydroxychloroquine sulfate, donated to the Strategic National Stockpile, to be used to treat certain hospitalized patients with COVID-19 when a clinical trial was unavailable or participation in a clinical trial was not feasible. The FDA said that the legal criteria for issuing an EUA were no longer met and that the drugs were “unlikely to be effective in treating COVID-19 for the authorized uses in the EUA”.

Appendix: How emergency use authorization is obtained

Emergency use authorization is legislated under section 564 of the US Federal Food Drug and Cosmetic Act, the original version of which dates from 1938.​

The processes involved are set out in a document titled “Emergency Use Authorization of Medical Products and Related Authorities. Guidance for Industry and Other Stakeholders”, issued in January 2017.​

The FDA can issue such authorization “not only during an emergency to support a rapid public health response, but also for significant potential of an emergency (e.g. in advance of an emergency)”.​

The primary criterion for authorization is that there is “a public health emergency, or a significant potential for a public health emergency, that affects, or has a significant potential to affect, national security or the health and security of United States citizens living abroad, and that involves a CBRN [chemical, biological, radiological or nuclear] agent or agents, or a disease or condition that may be attributable to such agent(s)​.”

Medicinal products and uses of medical products that are eligible for such authorization include those that are not already “approved, cleared, or licensed”.​

For medical interventions the following four statutory criteria must be satisfied:​

a. Serious or Life-Threatening Disease or Condition​
The CBRN agent to be treated “must be capable of causing a serious or life-threatening disease or condition”.​

b. Evidence of Effectiveness​
There must be evidence that the product “may be effective to prevent, diagnose, or treat serious or life-threatening diseases or conditions”. In the case of a therapeutic agent, the effect may include mitigation of the problem, not necessarily cure.​

c. Risk-Benefit Analysis ​
This is what is nowadays more commonly called assessment of the benefit to harm balance, recognizing that risk is a chance and benefit an outcome and that the two are not therefore commensurate. In this case the probability of the known and potential benefits of the product must outweigh the known and potential risks of harm due to the product. This assessment must take into account “the material threat posed by the CBRN agent”. It also takes into account “the totality of the scientific evidence”. This “may include (but is not limited to): results of domestic and foreign clinical trials, in vivo efficacy data from animal models, and in vitro data”. It also includes an assessment of “the quality and quantity of the available evidence, given the current state of scientific knowledge.”​

d. No alternatives​
​It is stipulated that “there must be no adequate, approved, and available alternative to the candidate product” or that “a potential alternative product may be considered ‘unavailable’ if there are insufficient supplies” or if it is “contraindicated for special circumstances or populations (e.g. children, immunocompromised individuals, or individuals with a drug allergy), if a dosage form of an approved product is inappropriate for use in a special population (e.g. a tablet for individuals who cannot swallow pills), or if the agent is or may be resistant to approved and available alternative products.”​

Information to support an application​
​The FDA recommends [but does not mandate] that a request for authorization should include “a well-organized summary of the available scientific evidence regarding the product’s safety and effectiveness, risks (including an adverse event profile) and benefits, and any available, approved alternatives to the product.”​

It recommends that the following information be submitted in any request:​

•   a description of the product and its intended use;​
•   a description of the product’s FDA approval status (e.g. whether the product is unapproved or whether it is approved but the authorization is for an unapproved use); whether the product or intended use is under an investigational application; whether the product is approved in a foreign country for either the proposed use or another use; information on such use;​
•   the need for the product, including identification of any approved alternative product(s) and their availability and adequacy for the proposed use, and the unmet need(s) the authorization would address;​
•   available safety and effectiveness information for the product;​
•   a discussion of risks and benefit (i.e. the benefit to harm balance);​
•   information on chemistry, manufacturing, and controls;​
•   information about the quantity available and potentially available by further manufacture;​
•   information comparable to an FDA-approved package insert or instructions for use.​
•   information in support of an extension of a product’s labelled expiry date (not relevant in this case);​
•   information on the right to rely on previously submitted evidence.​​

The FDA also outlines separately the type of “safety information”, i.e. information about potential harms, that should be submitted and “anticipates that, for some products, data from controlled clinical trials will be available. … FDA expects to interpret safety information in light of the seriousness of the clinical condition, alternative diagnostics, prophylaxis, or alternative therapies (if any), and the specific circumstances of the emergency or threat of emergency.”​​

Other data recommended for inclusion in an application include: ​

•   well-organized study reports that provide a complete assessment and analysis, including any statistical analyses, of available safety and effectiveness data and an interpretation of the findings. If final study reports are not yet available, any available interim study reports should be provided and clearly identified as such;​
•   source data for clinical studies, nonclinical laboratory studies, and any animal studies that contribute to assessing activity or effectiveness of the product in the treatment of the underlying disease or condition or a closely related disease or condition, such as case report tabulations for key studies; case report forms for all patients who died during the clinical studies and for all persons who did not complete the study due to an adverse event, regardless of causality; relevant reports in the published literature; and translations of source materials that are in a language other than English;
•   measures taken to mitigate risk or optimize benefit;
•   limitations, uncertainty, and data gaps;
•   a description of contraindications and cautions, such as are normally included in the label of a medicinal product.​

Termination of an authorization
An authorization may be terminated when the circumstances that precipitated the declaration have ceased or the approval status of the product has changed, such that the authorized use(s) of the product are no longer unapproved.​

Disclaimer: This article has not been peer-reviewed; it should not replace individual clinical judgement and the sources cited should be checked. The views expressed in this commentary represent the views of the authors and not necessarily those of the host institution, the NHS, the NIHR, or the Department of Health and Social Care. The views are not a substitute for professional medical advice.