COVID-19: US FDA grants emergency authorisation for remdesivir

EUA doesn't equal final nod; China trial painted different picture

By Banjot Kaur
Published: Saturday 02 May 2020
Transmission electron micrograph of the novel coronavirus (SARS-CoV-2) particles, isolated from a patient Photo: NIAID/Flickr__

The United States Food and Drug Administration (FDA), on May 1, 2020, granted Emergency Use Authorization (EUA) of anti-viral drug remdesivir for patients of the novel coronavirus disease (COVID-19).

The broad-sprectrum antiviral medication has been developed by US-based Gilead Sciences Inc, an American bio-pharmaceuticals company.

A review of top line data from the randomised, double-blinded, placebo-controlled trial of remdesivir by the National Institute of Allergy and Infectious Diseases (NIAID) and from an open trial of the drug sponsored by Gilead Sciences was conducted, according to the FDA.

“It is reasonable to believe that the known and potential benefits of remdesivir outweigh the known and potential risks of the drug for the treatment of patients hospitalised with severe COVID-19,” the FDA said in a letter to Gilead Sciences.

The drug will be given intravenously in hospital settings. Gilead will have to report adverse events to the FDA.

EUA no approval

An EUA given by the FDA does not guarantee approval of any product. “The EUA allows for the distribution and emergency use of remdesivir only for the treatment of COVID-19,” Gilead Sciences said in the statement.

Remdesivir remains an investigational drug and has not been approved by the FDA, the statement said.

The FDA commissioner may allow ‘unapproved’ medical products to be used in an emergency diagnosis, treatment or to prevent serious or life-threatening diseases or conditions, under section 564 of the Federal Food, Drug and Cosmetic Act (FD&C Act).

The conditions listed in the act include those caused by chemical, biological, radiological and nuclear defense (CBRN) threat agents when there are no adequate, approved and available alternatives.

Such an authorisation by the FDA has to be necessarily preceded by a declaration of a health emergency — for which there is no approved drug — by the US Health and Human Services (HHS) secretary.

When the HHS secretary declares that an emergency is over, the EUA declaration is terminated. It also stands terminated by default if the status of the product changes to ‘approved’ by the FDA

A product may be considered for EUA if the commissioner determines the known potential benefits of the product outweigh its known and potential risks, according to the FDA.

Such an EUA, however, makes it mandatory for the drug producer to come up with detailed information, coupled with a general fact sheet — that details usage and potential harmful effects — for healthcare professionals.

An informed consent from recipients is also required “to the extent practicable given the applicable circumstances”, since the drug is unapproved.

“Gilead will supply remdesivir to authorised distributors or directly to a US government agency who will distribute to hospitals and other healthcare facilities as directed by the US government, in collaboration with state and local government authorities, as needed,” said the letter to Gilead by the FDA.

China vs US

Anthony Fauci — director of NIAID and a key member of the US task force on COVID-19 — was confident on April 29 about the results of a clinical trial conducted on the drug by his institute.

“Data shows that remdesivir has a clear-cut, significant, positive effect in diminishing the time to recovery,” he said.

Hospitalised patients at advanced stages of COVID-19 and lung involvement, who received remdesivir, recovered faster than those who received a placebo, the NIAID claimed in a statement on April 29.

This was according to a preliminary data analysis from a randomised, controlled trial that began on February 21, involving 1,063 patients, the statement said.

The NIAID results — on the basis of which the FDA granted the EUA — however, have not been published in any peer-reviewed scientific journal yet.

The trial was also criticised on the count that outcomes were changed.

‘Death’ was removed as the primary outcome from the trial as originally intended, said Didier Raoult, a renowned infectious diseases expert and head of France’s Marseille University Hospital Institute for Infectious Diseases.

On the same day, the results of another randomised controlled clinical trial — led by The Chinese Academy of Medical Sciences — were published by medical journal The Lancet.

The results of the trial showed remdesivir had no significant clinical benefits for COVID-19 patients.

“Our trial found that intravenous remdesivir did not significantly improve the time to clinical improvement, mortality or even the time to clearance of virus in patients with serious COVID-19 compared to placebo,” the paper said, claiming that it was the first randomised controlled trial of the drug on COVID-19 patients.

Placebo refers to the group of patients enrolled for the trial who were given an inactive form of the drug in comparison to those who were given an active form.

Such a trial is known as a ‘controlled trial’ in medical parlance. The word ‘randomised’ was used as COVID-19 positive patients above 18 years of age were randomly selected.

The trial, however, had a very serious limitation: It was ‘underpowered’, that is, it could not enrol the targeted number of patients. Only 237 patients were enrolled, against a target of 453.

The two most important trials on the drug, thus, have glaring limitations: While one was yet to be published in a peer-reviewed journal, the other was ‘underpowered’.

The World Health Organization (WHO), meanwhile, is yet to issue a statement on the EUA. It did, however, publish the draft findings of the Chinese Academy on its website on April 25, before The Lancet published it.

The WHO later removed the draft findings from its website, saying they were “mistakenly” published.

Remdesivir is, incidentally, not the first drug to be given EUA as portrayed by many national and international media outlets.

The FDA earlier granted similar approvals for hydroxycholorquine (HCQ) for COVID-19 patients in hospital settings. The drug, however, did not generate as much talk in the US as remdesivir did.

HCQ is cheaper than remdesivir.

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