On Sunday, Food and Drug Administration Commissioner Stephen Hahn issued an emergency use authorization, or EUA, for plasma therapy to treat COVID-19—and a flurry of criticisms quickly followed.* Critics argue that President Donald Trump pressured Hahn to issue the EUA and that further testing should have been done before the therapy was recommended. Arguments over the legitimacy of EUAs are quickly becoming something akin to the mask wearing debate, where political rivals square off over an issue of great importance to public health. But frustrations with Trump and Hahn aside, issuing the plasma EUA was a good decision, and too strong a backlash threatens the existence of this valuable public health tool.
EUAs were introduced in 2004 with passage of the Project BioShield Act, which updated the Food, Drug, and Cosmetic Act, and empowered the FDA commissioner to authorize emergency use of unapproved drugs, medical devices, and other health care products, such as diagnostic tests. The commissioner can issue EUAs to treat or prevent serious or life-threatening conditions caused by chemical, biological, radiologic, and nuclear agents when there are no adequate, approved, and available alternatives. Imagine that a terrorist group attacks the United States with an unknown biological weapon, and we have no treatments for the illness that results. Under those circumstances, many people could die unless we take reasonable risks by rapidly deploying unapproved treatments to address the illness. The anthrax attacks after 9/11 demonstrated the need for rapid deployment of experimental treatments, and the first EUAs were issued in 2005 for an anthrax vaccine.
The traditional FDA approval process is designed to keep consumers safe under normal conditions. However, it is poorly adapted to the rapidly shifting conditions of a national emergency. Shepherding a drug through an entire series of clinical trials can take up to 10 years and require hundreds or thousands of research subjects. That is where EUAs come in. They provide exceptions to the FDA approval process under extraordinary circumstances. Before COVID-19, they were uncommon. But the pandemic is unique. Unlike isolated terror attacks or other infectious disease outbreaks, it is a global event affecting millions, and we have no effective treatment for the virus. In the past six months, EUAs have made many COVID-19 diagnostic tests, personal protective gear, and medical treatments available quickly.
Critics of the plasma EUA argue that the FDA should have waited for evidence from randomized controlled trials before it was issued. But that would defeat its purpose. The EUA is designed for use in response to public health and military emergencies in which a chemical, biological, radiologic, or nuclear threat is released and there are no adequate, approved, and available countermeasures. The whole idea is that there would be no time to conduct additional research before making a drug, device, or diagnostic test available. The Project BioShield Act specifies that though they may be desirable, clinical trials are not required, let alone randomized controlled clinical trials, or RCTs, which require hundreds of participants and a placebo control group. The requirements for issuing an EUA are intentionally low, and the FDA commissioner needs only a reasonable belief that the treatment will be effective. In the case of plasma therapy, the available data support that conclusion.
RCTs are the gold standard for drug development, but they are not the only source of valuable information. Thomas Frieden, a former head of the Centers for Disease Control and Prevention, has argued against blind devotion to randomized controlled trials as the sole basis for health decision making. According to Frieden, limitations such as cost and time constraints “affect the use of RCTs for urgent health issues, such as infectious disease outbreaks,” where decisions must be made quickly based on limited and imperfect information. This is not to say that RCTs are unimportant. They are crucial to the advancement of medical science.
However, if there was ever a time to look at other sources of data, it would be during a global pandemic, an event unlike anything contemporary society has faced. On March 10, Health and Human Services Secretary Alex Azar issued an emergency use declaration making COVID-19 EUAs possible. If feasible and appropriate, the FDA commissioner must consult with directors of the National Institutes of Health and the CDC before issuing each EUA. But the commissioner is not bound by their opinions. Afterward, he can issue an EUA if he concludes the inciting chemical, biological, radiologic, or nuclear agent can cause a serious or life-threatening condition, and based on the totality of the scientific evidence, it is reasonable to believe that the treatment may be effective in managing that condition. The reasonable belief requirement is intentionally low, and the Project BioShield Act specifies what kinds of information can be considered, including results from foreign and domestic clinical trials, in vivo experiments involving animals, and even in vitro data from lab tests involving no animals or humans. Finally, it must be reasonable for the commissioner to believe that the known and potential benefits of the treatment outweigh the known and potential risks, and there are no adequate, approved, or available alternatives.
One thing the critics get right is that the FDA should be more transparent about its rationale for issuing EUAs. The plasma EUA offered scant details on how the FDA reached its conclusions, and it certainly did not help matters that on Sunday, when the EUA was announced, Trump incorrectly claimed the plasma therapy reduced COVID-19 mortality by 35 percent. The statement was echoed by both Hahn and Azar. Critics pointed out that this was nowhere near correct; cardiologist and author Eric Topol tweeted that it was “[n]ot only blatantly wrong; an egregious public statement.” On Monday, Hahn apologized in a Twitter thread: “I have been criticized for remarks I made Sunday night about the benefits of convalescent plasma. The criticism is entirely justified. What I should have said better is that the data show a relative risk reduction not an absolute risk reduction.” There’s a big difference between relative and absolute here, and the administration overstated the therapy’s effectiveness based on current data. But that error is not a reason to reject the EUA altogether.
Critics also argue that the EUA will not generate adequate research data and will deter people from enrolling in ongoing or future clinical trials. There may be some truth to the claim that making treatments available by EUA might deter people from enrolling in trials, but that is not as bad as critics contend because EUAs can generate useful data. The FDA commissioner has broad discretion to attach conditions to an EUA, such as requiring that clinicians track the treatment’s use and report the results. To that end, Hahn included a provision requiring hospitals and health care workers administering COVID-19 plasma to track serious adverse reactions and report them to the FDA. He could go further and revise the EUA to collect more granular data.
The FDA could consider adding a condition to prioritize plasma therapy for patients who are critically ill, which would help alleviate concerns that the EUA will increase demand for plasma, leading to widespread shortage. It might also alleviate concerns that plasma therapy may expose patients to unnecessary risks. It is easy to forget that there are no adequate, approved, or available treatments for COVID-19, which means people in critical condition often die. The current EUA does not prioritize critically patients, but it does require patients to have been hospitalized.
Opponents use the FDA’s previous EUA for hydroxychloroquine as evidence that the EUA system might be dangerous. However, the hydroxychloroquine case is an example of the system functioning properly. Under the Project BioShield Act, an EUA is only the start of a longer process. The FDA should monitor the situation, and if a treatment turns out to be harmful or ineffective, then the EUA can be revised or revoked. That is what happened to chloroquine and hydroxychloroquine in mid-June.
During the pandemic, senior public health officials outside the FDA appear to claim that requirements for making medical products available during national emergencies should rise to the level of randomized clinical trials. But that is not required by the Food, Drug, and Cosmetic Act, and it should not be.
Hahn and Azar announced the plasma EUA with great fanfare. At this stage, they were wrong to tout plasma therapy as a major advance in the treatment of COVID-19. However, it was reasonable for Hahn to believe that the potential benefits of plasma outweigh the risks, and their press conference fumbles should not inhibit the use of EUAs in general. If the requirements for EUAs are made too stringent and approach the requirements for regular FDA approval, then our regulatory system will become too rigid to respond to future emergencies or even to shifting conditions of the current pandemic.
The United States was unprepared for COVID-19, and the emerging political debate over EUAs should not undermine this important public health tool.
Correction, Aug. 25, 2020: This article originally misidentified Stephen Hahn as the acting commissioner of the Food and Drug Administration. He is the commissioner, not the acting commissioner.