Bioethics Forum Essay

Ethics of Emergency Use Authorization During the Pandemic

During the first week of October, the Food and Drug Administration released guidance on data submitted by vaccine manufacturers for an emergency use authorization during the Covid-19 pandemic. The FDA’s rigorous guidance was met by resistance from the White House, since some of the terms would make it virtually impossible to issue an emergency authorization for a Covid vaccine before Election Day.

With the emergency use authorization process in a swirl of controversy, understanding the ethical dimensions of issuing it for a vaccine can provide clarity on the necessity of stringent guidelines from the FDA.

Under Section 564 of the Federal Food, Drug, and Cosmetic Act and an amendment by the Project Bioshield Act of 2004, emergency use authorization gives the Department of Health and Human Services and the FDA the power to authorize and distribute unapproved medical products (drugs, biologics, and devices) for a particular public health emergency and to authorize and distribute medical products that are approved for indications other than the particular health emergency.

Several criteria must be met for an emergency authorization: 1) the disease or condition must be serious or life-threatening; 2) there must be a “reasonable” belief that the product may be effective for diagnosis, treatment, or prevention, with the known and potential benefits outweighing the known and potential risks; and 3) there must be no adequate, approved, available alternative.

Three treatment-related emergency use authorizations have been issued during the Covid-19 pandemic. One of them has been revoked by the FDA, and two of them rely on weak or mixed data.

On March 28, the FDA issued an emergency use authorization for chloroquine and hydroxychloroquine, drugs approved for the treatment of malaria and the management of rheumatoid arthritis and lupus. However, the data used for the authorization involved few patients (one study consisted of only 100 patients and the other had only 36 patients) and were of low quality. For example, one of the studies was not blinded, lost numerous patients to follow- up, and relied on surrogate endpoints of unclear connection to clinical outcomes. Studies with such unreliable data should never be used to justify an emergency use authorization.

FDA revoked this authorization on June 15, after well-controlled randomized trials demonstrated no benefit from the drugs and reports of serious cardiac adverse events surfaced.

On May 1, the FDA issued an emergency use authorization for remdesivir—an anti-viral that had not yet been FDA-approved for any indications—for patients with severe Covid-19. It was issued on the basis of three prospective randomized studies of patients with moderate and severe Covid. On August 28, the FDA expanded the emergency use authorization to include all hospitalized Covid-19 patients, based on data from two randomized studies that included patients with mild and moderate illness.

However, on October 15 the World Health Organization’s Solidarity trial released interim results on mortality for four repurposed antiviral drugs, including remdesivir. The findings suggest that remdesivir has no definite effect on mortality, ventilation initiation, or time to hospital discharge. Further research is needed to determine whether the drug adds real benefits over the current standard of care for severe Covid-19. Despite the WHO’s findings, however, on October 22 the FDA approved remdesivir for hospitalized patients with Covid. Because the approval does not cover all Covid patients, the emergency use authorization remains in place for those who were excluded from the approval, such as some pediatric Covid patients.

The FDA issued the third emergency use authorization on August 23 for convalescent plasma, an unapproved treatment. However, there were no well-controlled prospective trials showing that convalescent plasma affected the course of Covid-19. Data from the National Expanded Access Treatment Protocol sponsored by the Mayo Clinic suggest a potential effect on mortality in hospitalized patients, but this was not a randomized controlled trial and the findings were based on a post-hoc review.

In its guidance on emergency use authorization for Covid vaccines, the FDA proposed rigorous requirements for evidence. Most importantly, the FDA recommended that a vaccine candidate reduce occurrence or severity of the disease in at least 50% of patients. Furthermore, safety data should have a median follow-up of at least two months and the manufacturer should submit a plan for active safety follow-up.

Despite the initial pushback from the White House, the FDA guidance for a vaccine emergency use authorization remains, and it is appropriate—the nature of vaccine development suggests that a certain degree of caution is ethically necessary.

First, if a Covid-19 vaccine does not have some reasonable level of efficacy, then the pandemic may be worsened rather than improved by its availability. A subpar vaccine could give people who take it a false sense of security, which could undermine other necessary public health measures that have helped to curb the spread of the virus: if individuals think that they are immune to the virus because they have been vaccinated, then they may fail to wear masks and practice social distancing.

Second, unlike drugs, a vaccine will be administered to millions of healthy individuals, making rigorous safety oversight imperative. The FDA and Centers for Disease Control and Prevention  have a number of post-approval surveillance systems in place, including the Vaccine Adverse Event Reporting System, the Vaccine Safety Datalink, and the Clinical Immunization Safety Assessment Project.

Although these systems will capture severe adverse events that can prompt renewed attention to the safety of a Covid-19 vaccine, post-market surveillance is most optimally used to complement robust pre-approval data, not to substitute for it. If a major safety concern occurs that could have been caught prior to large-scale distribution, public trust in vaccines could be irreparably undermined.

A cautious approach to safety data is even more important given that vulnerable populations—such as the older people and racial minorities that have been disproportionately impacted by the pandemic—will likely be given priority for access to the vaccine. It would be ethically impermissible to risk their safety and undermine their trust by distributing an understudied vaccine.

Prior emergency uses authorizations issued during the pandemic have been embroiled by controversy over the sufficiency of data used to support a determination of reasonable safety and efficacy. Unfortunately, political pressures may have led to the FDA making decisions in these cases that were not well-supported by science. With a Covid-19 vaccine, the FDA has a chance to win back the public’s trust by demonstrating that it will hold any candidates for an emergency use authorization to a high standard.

Beatrice Brown is a research assistant in the Program on Regulation, Therapeutics, and Law (PORTAL) in the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital, and she recently received her Master of Bioethics from Harvard Medical School. Twitter: @Beatrice__Brown.