A few weeks ago, the World Health Organization rejected the use of Gilead Sciences’s remdesivir for hospitalized patients with COVID-19, regardless of disease severity. This decision is in direct contrast to the US Food and Drug Administration’s emergency use authorization (EUA) of the drug, and President Donald Trump’s glowing endorsement. It’s also a reflection of the steep price of EUAs—the price of undermining medical science.
The FDA can grant an EUA to a drug to treat COVID-19 to facilitate the distribution of new therapeutics when there are no alternatives. EUAs are an important tool during the early stages of any pandemic because they loosen restrictions on novel treatment options. The problem is that they end up interfering with clinical trials that would provide the best evidence on whether these drugs are safe and effective.
The EUA means it is “reasonable to believe” that the drug “may be effective.” This “may be effective” standard is a much lower level of evidence compared to the “effectiveness” standard the FDA uses for product approvals. In addition to remdesivir, the FDA has granted EUAs to three therapies: convalescent plasma, a monoclonal antibody drug called bamlanivimab, and, most recently, Regeneron’s cocktail of monoclonal antibodies casirivimab and imdevimab, the very ones taken by President Trump when he contracted SARS-CoV-2. The FDA previously granted and revoked EUA status for hydroxychloroquine.
Randomized clinical trials (RCTs) are the gold standard for developing new drugs and vaccines. Patients are randomly assigned to either the control group receiving a placebo or to the treatment group receiving the experimental drug. RCTs are the foundation for the “first, do no harm” tenet of medical practice—for ensuring a drug’s safety and making informed decisions about whether the benefit of a new drug exceeds its dangers. But in a rush for COVID-19 treatments, we started throwing spaghetti on the wall, looking to see what sticks. And some, such as hydroxychloroquine and remdesvir, aren’t sticking, and things are getting messy.
Too many COVID-19 EUAs enhance the politicization of medical science and pollute the water for future research to get long-term answers.
In the case of hydroxychloroquine, a drug that is often prescribed to treat rheumatoid arthritis, its use to treat COVID-19 was highly publicized, politicized, and polarized. The FDA granted hydroxychloroquine EUA status on April 27, and less than two months later, on June 15, it was revoked after it became clear that at least one study supporting its use was based on questionable data and new scientific evidence showed that it had little to no effect in treating COVID-19 patients. Other research even indicated adverse events in patients who took it.
In all cases, even if a drug does turn out to be effective, granting a therapy EUA before it has completed clinical testing undermines the data and stunts the ability to properly collect and analyze that information to ultimately inform treatment decisions. When the FDA granted an EUA for remdesivir, our clinical trials on the drug came to a stop. Patients are less inclined to join a trial, in which they may or may not receive the drug, when they can just ask and receive the treatment that has been granted EUA status. And it’s unethical to ask a patient to participate in a clinical trial in which they may not receive treatment that has been approved by the FDA.
According to ClinicalTrials.gov, there are a few “active” clinical trials for current COVID-19 EUA therapies, and their progress and enrollment numbers are unknown. While EUAs are much needed, there should be more rigorous guidelines put in place to ensure that the clinical trials run their course before an EUA is granted. And, if an EUA is granted before that can happen, there needs to be a clearly defined plan to properly study the therapy post-authorization with new, updated protocols.
With respect to the COVID-19 therapies that have or will receive an EUA from the FDA, the good news is that authorization is temporary. The status can be revoked at any time, and such products have to be subjected to rigorous RCTs before receiving long-term FDA approval. What needs to be done now is to sort through the existing treatment options to determine which ones really work. President-elect Joe Biden’s administration should form an advisory panel to evaluate and reach some agreement on enabling and prioritizing studies of EUA treatments. This panel would establish priorities based on the limited data available on the COVID-19 drugs that have been granted EUA and new agents as they become available.
Sorting through this will be difficult because it creates ethical, financial, regulatory, and medical dilemmas. Patients need and require treatments and it is the doctors’ moral responsibility to “first, do no harm” and care for their patients with whatever treatments are at hand. Drugs cost money and clinical trials offer the potential treatments for free, while many insurance companies may not foot the bill for experimental EUA treatments. But if the use of multiple EUA drugs continues, without proper rigorously controlled clinical trials, we may never learn what is most effective and least harmful. Too many COVID-19 EUAs enhance the politicization of medical science and pollute the water for future research to get long-term answers. Going forward, we need approved therapies and national guidance on COVID-19 care and treatment.
Kevin J. Tracey is the president and CEO of the Feinstein Institutes for Medical Research, where Christina Brennan is the vice president of clinical research. At the start of the pandemic, Tracey and Brennan established a 200-person COVID-19 Clinical Trial Unit (CCTU) at the Feinstein Institutes to conduct controlled clinical trials to study the safety and efficacy of experimental COVID-19 therapies. Under their leadership, the research center has initiated seven clinical trials and programs and enrolled more than 1,200 participants.
Correction (December 6): This story has been updated to reflect that remdesivir is made by Gilead Sciences, not Regeneron. The Scientist regrets the error.