Remdesivir, the first COVID-19 drug to be approved by the U.S. Food and Drug Administration (FDA), was once hailed as the life-saving drug for hospitalized patients with severe COVID-19 infection. Despite emerging studies indicating it is not effective for inpatient treatment, and a declaration by the World Health Organization (WHO) that remdesivir does not reduce mortality or duration of hospitalization, it is still being used in several countries to treat COVID-19. Remdesivir appears to have been rushed through the emergency use authorization (EUA) process by its sponsor, the National Institute of Allergy and Infectious Diseases (NIAID) – a branch of the National Institutes of Health (NIH) – and trial study endpoints on the impacts of remdesivir were modified to make remdesivir appear more successful in fighting the virus. Dr. Fauci, Director of the NIAID, declared remdesivir the “new standard of care.” By May 2020, a EUA ensured that Gilead – the manufacturers of remdesivir – could monetize the drug. Several months later, the FDA approved formally. As the pandemic continues, and safety issues and concerns of an automatic use in certain conditions merit, TrialSite takes another look at what is actually, a troubling situation.
Research resulting in the development of remdesivir began as early as 2009, and antiviral profiling in 2013 and 2014 showed potential in using remdesivir against virus outbreaks. The University of Alabama at Birmingham (UAB) was instrumental in developing remdesivir for antiviral use through research conducted by their Antiviral Drug Discovery and Development Center.
UAB was awarded a $37.5 million grant from the NIAID to study and develop a treatment for emerging viruses. The grant was a multi-institutional collaboration, and a public-private partnership between several academic institutions and Gilead Sciences, Inc. (Gilead). The grant led to the development of remdesivir, which was originally developed to treat the coronavirus causing Middle East respiratory syndrome (MERS).
The taxpayer has been a partner to the remdesivir enterprise, thanks to public funds continuously allocated between 2000 and 2019. The NIH provided $6.5 billion for research of various antiviral treatments with approximately $161.5 million directed to remdesivir preclinical studies and clinical trials from 2013.
The continued development and manufacture of remdesivir was done by Gilead, one of the world’s largest biotech corporations based in the San Francisco Bay Area in collaboration with the U.S. Centers for Disease Control and Prevention (CDC), and the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIDD), part of the Department of Defense (DOD). In its quest to prepare for pandemics, the U.S. government pursued investigational treatments for RNA-based viruses, such as EBOV (Ebola virus), MERS, and severe acute respiratory syndrome (SARS). Despite widespread public development and funding of remdesivir, the patent is owned by Gilead.
Remdesivir as a Dangerous Ebola Treatment
When the Ebola outbreak occurred in 2013 – 2016, scientists discovered that remdesivir reduced replication of EBOV in nonhuman primates. It was also discovered that remdesivir had antiviral capabilities against other viruses, including the coronavirus MERS. Following these discoveries, more researchers tested the antiviral activity of remdesivir, and it was confirmed against SARS, MERS, zoonotic coronaviruses, and human coronaviruses.
Based on the nonhuman primate studies of remdesivir on Ebola, Gilead pursued FDA evaluation of remdesivir use in humans under the FDA’s Animal Rule which permits the reliance on efficacy findings from animal studies for drugs that are not ethical to conduct human trials.
Driven by the ongoing Ebola outbreak, remdesivir was included in a randomized, controlled trial of Ebola virus therapeutics in patients from the Democratic Republic of Congo. Mid-study primary analyses found that remdesivir was inferior to other antibody-based therapeutics (including ZMapp, Mab114, and REGN-EB3), concerning mortality. On day 28 after infection, the EBOV mortality rate for remdesivir was 53.1%, and the remdesivir use was halted as a treatment for humans with Ebola. Adverse events were also reported, including hypotension and elevated creatinine levels, as well as impaired kidney and liver function.
In April 2020 Dr. Anthony Fauci claimed that remdesivir was safe, based on COVID-19 investigation. Yet, previous research during the EBOLA investigations raised questions.
Remdesivir used against COVID-19
As remdesivir was known to inhibit replication of coronaviruses before the current COVID-19 pandemic, Wang et al. (2020) published that remdesivir, when used with other antivirals, could inhibit SARS-CoV-2 (the virus that causes COVID-19) replication. The authors of the study are all affiliated with the Wuhan Institute of Virology, which has in the past received funding from the NIH for virology research. Gilead facilitated emergency access to remdesivir through a compassionate use program for COVID-19 patients with severe disease and no access to a clinical trial.
In February 2020, a placebo-controlled clinical trial (ACTT) was launched by the NIH and conducted in 60 locations and 10 countries to evaluate the effectiveness of remdesivir in preventing death in hospitalized adults diagnosed with COVID-19.
On April 28, 2020, Fauci announced that the trial showed a significant improvement of 31% in time to recovery for the remdesivir group, describing this as “clear cut evidence that the drug works.” He predicted that remdesivir would become the new standard of care for COVID.
Based on results from the NIH funded ACTT-1 trial (NEJM JW Infect Dis Dec 2020 and N Engl J Med 2020; 383:1813), remdesivir became the first antiviral drug approved by the FDA as a treatment for SARS-CoV-2 infection and is recommended for treatment of hospitalized patients who require supplemental oxygen but not mechanical ventilation (NIH COVID-19 Treatment Guidelines. opens in new tab). But this was no slam dunk. As discussed below, some large clinical trials failed to produce a remdesivir benefit (N Engl J Med. 2021;384:497. opens in new tab).
NIAID Trial: Moving the Goalposts
TrialSite reported in “Not a Knockout Drug but Knocking it out of the Ball Park: Gilead Windfall as Remdesivir COVID-19 Sales to Hit $1 to $3 Billion in 2020” that the success of remdesivir was made possible by NIAID-funded adaptive clinical trial where the sponsor allowed a questionable change in the trial endpoint, part of what helped the FDA comes to the EUA determination.
After the NIAID director declared “a new standard of care,” he stressed that it most certainly wasn’t a “knock-out drug.”
In his pronouncements, Fauci failed to explain that late in the study the NIAID changed the primary outcome for measuring the success of remdesivir as a treatment for coronavirus.
Initially, the primary outcome of the study had been listed as “Percentage of subjects reporting each severity rating” on Day 15. This was originally based on a 7-point scale, which was then changed to an 8-point scale on March 20, 2020. In both scales, death was included as the most severe outcome; however, the scale was changed to split the category of “hospitalized, not requiring supplemental oxygen” into two: one still requiring medical care, and one not.
On April 16, 2020, the primary outcome of the study was changed to “time to recovery,” which was a new outcome based on the three least severe outcomes from the point scale used previously, including the newly created category for hospitalized patients that did not require medical treatment.
While changing outcomes in clinical trials is not necessarily a problem and can occur—the ACTT-1 trial was an adaptive after all, the decision must be declared and justified when results are announced to avoid false positives and misleading external evaluators and readers. The paper resulting from the trial, published in October 2020, states that the change in the primary outcome was made “in response to evolving information, external to the trial, indicating that COVID-19 may have a more protracted course than previously anticipated.” Given the urgency early in the pandemic, significant risk-benefit tradeoffs are understandable. Yet several economical, repurposed drugs were identified as significant potential candidates targeting COVID-19. But the NIH had little interest in these pursuits. Remdesivir seemed like the “chosen one.”
EUA to Approval
Remdesivir’s initial EUA based on ACTT-1 allowed for the drug’s immediate use to treat severe COVID-19 infections on May 1, 2020. The EUA was expanded in August 2020 to include treatment of all hospitalized COVID-19 patients, regardless of the severity of infection.
By October 2020, the FDA approved remdesivir for treatment of hospitalized patients who are 12 years of age or older, weighing more than 40 kilograms (88 lbs.). The approval of remdesivir was supported by the FDA’s analysis of data from randomized, controlled clinical trials of hospitalized COVID-19 patients, including the NIAID trial, the Gilead-funded trial which didn’t have a control group, and a second Gilead-funded trial whose authors questioned the importance of their own findings. “We are pleased that the FDA approved Remdesivir for COVID-19 treatment and that our organization added value to this global fight through its early support of this critical drug’s development,” said Douglas Bryce of the U.S. Department of Defence (DOD).
The drug was formally approved in October 2020. As the only FDA-approved COVID drug between May 2020 and November 2021, it is estimated that remdesivir has been prescribed to 50% of COVID patients in U.S. hospitals – making Dr. Fauci’s prediction of the reach of this drug come true. The company generated several hundred millions of dollars in revenue during the worst parts of the pandemic before it was even formally approved.
How Did Gilead Benefit from Remdesivir?
A big part of successful drug development includes the capitalization of the research expenditures of the public. The decades of public funding culminating in the COVID-19 pandemic ultimately led to Remdesivir’s rise, a windfall for Gilead. Based on research conducted by the United States Government Accountability Office (GOA), federal funding for remdesivir between 2013 and December 2020 totaled at least 161.5 million divided as follows:
$0.7 million for CDC’s preclinical research
$39.7 million for DOD’s preclinical research
$11.9 million for research conducted by NIH and NIH-funded universities
$109.2 million for NIH-funded clinical trials
The federal funding did not result in governmental patent rights of remdesivir, as it did not lead to the development of new inventions.
According to Gilead, the company did not rely on federal contributions to conduct research into the invention of remdesivir, and instead invested $786 million into remdesivir research in development from 2000 to 2020. But clearly, taxpayer funds supported this drug through the early stages of the pandemic and extensively before.
According to an article published in October 2020, Gilead earned nearly $900 million from sales between July and September 2020—only the vaccines from Pfizer and Moderna surpass such a rapid windfall later on. It also comes as no surprise, based on the financial gains of Gilead, that eight experts on the NIH COVID-19 Panel have financial ties to Gilead, according to the NIH’s COVID-19 Treatment Guidelines Panel Financial Disclosure for Companies Related to COVID-19 Treatment Diagnostics document. TrialSite however has no proof of any explicit conflict of interest—we only raise the data points for those interested in possibly learning from the past. Despite remdesivir treatment costing $9.32 to produce, the treatment is said to cost more than $3,100 in hospitals in the U.S.
It is reported that Gilead spent $2.45 million lobbying the U.S. Congress in the first quarter of 2020, more than ever before, with a 32% increase from 2019. This coincided with the drafting and passing of the Coronavirus Aid, Relief, and Economic Security Act, which includes funding for the development of treatments for COVID-19.
In the world of business, of course, Gilead did exactly what it was supposed to do. Corporations exist to drive revenue, profit, and importantly, growth and subsequent economic value return for shareholder value. In such an urgent, emergency setting as the COVID-19 pandemic, any reform or temporary pause in expected self-interested behavior, for example, requires dialogue and alignment of interests with large institutional equity holders—a topic far beyond this media.
Questions Arise: The WHO Solidarity Study
The WHO conducted the world’s largest randomized controlled trial on COVID-19 therapeutics called the Solidarity Therapeutics Trial. The trial is ongoing and includes 14,200 hospitalized patients from 600 hospitals in 52 countries. The trial primarily looks at “the effects…on overall mortality, initiation of ventilation, and duration of hospital stay in hospitalized patients.”
On October 15, 2020, WHO released interim results from the trial in a press release, stating that “remdesivir, hydroxychloroquine, lopinavir/ritonavir, and interferon regimes appeared to have little or no effect on 28-day mortality or the in-hospital course of COVID-19 among hospitalized patients.”
Despite these interim results and ensuing announcements by many nations to suspend use of the drug for COVID-19 patients, many countries continue to use remdesivir as inpatient treatment. By November 2020, after the WHO press release, Gilead reported that remdesivir continued to be “the first and only approved antiviral treatment for patients with coronavirus in approximately 50 countries.” Although a conclusive list of countries using remdesivir is not available, it appears that it is still being used by major economic powers, and has been approved or received EUA to treat COVID in India, Singapore, Japan, the European Union, the United States, Canada, Czech Republic, and Australia, although since the WHO findings many countries in Europe and elsewhere suspending use.
Safety Concerns with the Use of Remdesivir
As remdesivir continues to be used in several countries to treat COVID-19, data continues to emerge regarding its usefulness and safety. Most initial data regarding the safety of remdesivir came from clinical trials conducted to support the EUA.
A paper by Singh and Kamath (2021) published in Expert Opinion on Drug Safety assessed the adverse events associated with remdesivir use using real-world data. The authors looked at the FDA Adverse Event Reporting System (FAERS) and analyzed adverse events more frequently reported with remdesivir compared to other COVID-19 drugs. The study found that elevated liver enzymes, acute kidney injury, raised blood creatinine levels, bradycardia, cardiac arrest, and death had a disproportionately higher reporting with remdesivir than compared to other drugs.
Researchers from the University of Cincinnati also conducted a study into the effectiveness of remdesivir and found that remdesivir stops activity associated with CES-2, an enzyme required for the breakdown of several medications in the intestines, liver, and kidneys. This cautions against the use of remdesivir along with other drugs, as “this finding provides a mechanistic explanation to the observed high rate of serious adverse events and mortality with the use of remdesivir.”
This result comes as no surprise when considering the adverse events, including kidney and liver damage, hypotension, and elevated creatinine levels reported when the drug was used against Ebola. Indeed, with the widespread use of remdesivir in U.S. hospitals, there is speculation that the adverse effects of this drug could possibly be contributing to the deaths chalked up to COVID-19. Discussions with several critical care physicians, who wish to remain anonymous, raised concerns about use of the drug so uniformly on COIVD-19 patients in hospital settings.
Looking Forward
Regardless of negative findings and problematic data points, influential medical societies in the U.S. such as the Infectious Disease Society of America (IDSA) point to strong support and an absolute acceptance in an overall benefit promoting widespread use during the pandemic.
With new variants of SARS-CoV-2 emerging and evidence of remdesivir resistant strains mutating, questions of remdesivir efficacy and safety for COVID-19 patients persist. Despite the WHO Solidarity findings and subsequent recommendations, not to mention mounting safety issues, several countries continue to depend heavily on remdesivir as a treatment against COVID-19.
In the pursuit of objective, unbiased medical research, transparency, accessibility, and stakeholder engagement, TrialSite will continue to monitor the global use of remdesivir, as well as emerging safer and more effective alternatives for COVID-19.
