The United States Food and Drug Administration (FDA) focuses on implementing and following procedures to ensure that the products it regulates are safe and effective.  As many in the regulated industries can attest to, sometimes disruptions occur.  Nevertheless, no one could have predicted the disruption brought by the COVID-19 virus in 2020.  This article will explore some areas in which FDA’s procedures were disrupted in 2020 and what the “new normal” might look like in 2021.

Emergency Use Authorizations

Before 2020, emergency use authorizations (“EUAs”) from FDA were familiar only to “FDA nerds.”  Now, EUAs are at the forefront of the daily news and were the topic of discussion at nearly every Zoom Thanksgiving dinner. 

EUA Standards and Approvals

The Federal Food, Drug, and Cosmetic Act (“FD&C Act”) permits emergency use of a product that “is not approved, licensed, or cleared for commercial distribution” or that is approved but the proposed use is not approved.[1]  For an emergency to exist and permit FDA to issue EUAs, the Secretary of the Department of Health and Human Services (“HHS”) must determine that there is “a public health emergency, or a significant potential to affect, national security or the health and security of United States citizens living abroad, and that involves a [chemical, biological, radiological, or nuclear] agent or agents, or a disease or condition that may be attributable to such agent(s),” which includes emerging infectious diseases.[2]  The FDA Commissioner may then permit EUAs within the scope of the declared emergency. 

With novel and rapidly changing threats, FDA has some flexibility in authorizing EUAs.  EUAs for unapproved product uses are analyzed “based on the totality of scientific evidence available.”[3]  Using the evidence FDA has available, FDA may grant an EUA if “it is reasonable to believe that the product may be effective for the specified use.”[4]  FDA looks at a “may be effective” standard for EUAs, but with a non-emergency, routine approval FDA will look at a product’s “effectiveness,” which is a more exacting standard.[5]

With the COVID-19 pandemic, EUAs focused not only on treatment, but also on supporting equipment, including personal protective equipment (“PPE”), ventilators, and diagnostics.  With a novel virus, the immediate focus was on prevention, causing a scramble for PPE.  For example, in March 2020, FDA addressed which filtering facepiece respirators, i.e., masks, are authorized to be decontaminated and reused by medical staff, requiring that the decontamination process have its own EUA.[6]  Even with an ongoing shortage of PPE, attention turned to supportive care, and FDA created the Coronavirus Treatment Acceleration Program (“CTAP”).  With CTAP, FDA is able to track new treatments, including the use of antivirals, cell and gene therapies, immunomodulators, neutralizing antibodies, and many other treatments.[7]

As we have seen in the last few weeks, FDA has begun reviewing clinical studies and data to support EUAs for vaccines.  Although the vaccines have been developed at breakneck speed, the clinical trials have enrolled tens of thousands of study participants in order to obtain the data needed for EUA or eventual full approval.  On December 11, 2020, FDA granted Pfizer’s vaccine authorization for emergency use.  Pfizer’s “late-stage clinical trial, which enrolled nearly 44,000 people, was . . . 95 percent effective,”[8] and FDA’s approval demonstrates that “the known and potential benefits outweigh the known and potential risks of the vaccine.”[9] 

Unavoidable Pitfalls of EUA

FDA’s work during this national health crisis has been extraordinary, but that is not to say that everything has been perfect.  Though critics might say that “fast is the enemy of good,” that is somewhat misleading; FDA makes the best decisions it can with the information it has available. 

Facing immense pressure, on March 28, 2020, FDA granted an EUA for chloroquine phosphate and hydroxychloroquine sulfate to treat patients with COVID-19 “based on the science and data available at the time.”[10]  With its ongoing review of the most up-to-date data and clinical experience, however, on June 15, 2020, FDA revoked that EUA “in light of ongoing serious cardiac adverse events and other potential serious side effects,” finding that the potential treatment benefits “no longer outweigh the known and potential risks for the authorized use.”[11]

Our constantly changing body of knowledge about this novel virus is not limited to treatments.  Many diagnostic tests were granted EUAs at the beginning of 2020 in the hope of identifying infected individuals to slow the spread of the virus.  With some of these diagnostic tests, the Abbott ID NOW point-of-care test for example, early data suggests that these tests returned many false negative results.[12]  Particularly with a rapidly spreading and contagious virus, false negative tests can result in patients who think they are not contagious but are unknowingly infecting others.  Unfortunately, public confidence in FDA’s response to the pandemic took a bit of a hit with this, and FDA continues to face the difficult task of revoking EUAs when data suggests that the benefits no longer outweigh the risks.

Despite some speedbumps along the way, however, FDA has worked with industry to address these problems as they arise.  As Abbott’s point-of-care test has demonstrated, rigorously collecting data and analyzing it is key to having the most up to date understanding of this virus.  FDA has partnered with various companies and organizations, including Aetion,[13] the Critical Path Institute, and the National Center for Advancing Translational Sciences,[14] to focus on data collection and analysis. 

Operation Warp Speed

In a push to move treatments towards an EUA, Operation Warp Speed was established as a collaboration between the Department of Health and Human Services (HHS) and the Department of Defense.[15]  With Operation Warp Speed, a vaccine’s path to development is essentially the same, but components proceed simultaneously instead of step-wise.[16]  Additionally, the U.S. government would lend support to private companies and would oversee the clinical trial protocols.[17]

One of the ways that the government has provided substantial support is with involvement of the U.S. military.  We have seen how this pandemic has strained even the most robust supply chains, and that has been an ongoing concern for PPE, therapeutics, and other products such as needles and vials.  But for a vaccine to succeed, manufacturers needed to ensure they had all of the supplies ready to be able to distribute the vaccine once approved.  Here, for example, the military aided the vaccine manufacturers by ensuring they have all of the raw materials needed.[18] 

By all accounts, this operation was a success.  On December 11, 2020, about 10 months after the first recorded death from COVID-19 in the U.S., FDA issued an EUA for the first COVID-19 vaccine.[19]  Only a few days later, on December 14, the first individuals in the U.S. were given the vaccine.[20]  This worldwide pandemic has demonstrated that the government has the ability to pair its regulatory function (and sometimes financial resources) with industry’s infrastructure and R&D capabilities to lead to the development and approval of medical vaccines and therapies at an incredibly fast pace.  Going forward, these partnerships will be key to mitigating and solving healthcare crises as they occur.  Still, this success was not without setbacks, most notably the appearance of politicization of the FDA.

Political Pressure

Although FDA functions within HHS, which is part of the executive branch, FDA’s focus is on science, not politics.  FDA’s integrity is bolstered by three criteria: (1) “decisions should be based on a rigorous evaluation of the best available science, drawing on appropriate expertise, including the use of advisory committees”; (2) “decisions should be reached and documented through a process that promotes open-mindedness, with the bases of final decisions and processes for decision-making . . . adequately documented and explained”; and (3) “decisions should be made without inappropriate or external interference.”[21] 

As the current pandemic has thrown FDA and its decision-making into the spotlight, it is likely that as the crisis abates (even slightly), FDA will turn to these criteria more deliberately and publicly.  With additional transparency guided by these principles, FDA can garner confidence in its independence; this confidence will also be key to ensuring that an adequate number of individuals get a COVID-19 vaccine. 

FDA’s Use of Real-World Evidence and Future Advancements

As discussed with respect to EUAs, FDA has been using real-world evidence (“RWE”) to monitor and update its current thinking about a particular product or therapy.  The COVID-19 pandemic has shown FDA and industry just how important immediate, up-to-date data is to prevent the spread of the virus and to ease the burden on health care professionals.  In fighting this pandemic, not only do local and national government entities need to understand the effectiveness of certain devices or therapies, these entities also can use telemedicine or patient monitoring devices to get a more accurate view of disease progression and spread.

Most products approved by FDA have some post-approval monitoring, whether it is through a post-market safety study or reporting.[22]  In recent years, FDA has launched the Sentinel Initiative, which comprises a database focused on the safety of medical products.[23]  This initiative uses RWE, which has “eliminated the need for postmarketing studies on nine potential safety issues involving five products.”[24]  FDA acknowledges that using RWE can allow FDA “to provide patients and providers with important answers sooner – identifying a broader range of safety signals and following up on them more efficiently.”[25] 

With one vaccine already granted an EUA and more EUAs likely on the way, FDA has established a system using RWE to evaluate ongoing vaccine safety as the vaccines are distributed across the country.  Dr. Moncef Slaoui, who is on the Operation Warp Speed panel, stated that the panel is “working with the FDA and CDC to set up together a very, very high performance, active pharmacovigilance system that resembles almost to the day the assessment that we do in clinical trials to look at the safety of the vaccines in the population . . . .”[26]  Not only will the data collection be robust, “these data will be analyzed on a [day-by-day] basis.”[27]

The day-to-day analysis of vaccine safety data might be a signal that FDA is more willing to expand its use of RWE and/or telemedicine to track efficacy and safety outcomes.  For example, FDA has stated that “[s]oon, the FDA will have more to say in guidance about how to interpret [FDA’s] evidentiary standard in the context of today’s modern informatics and advanced analytics, which provide new openings for the collection of data and the generation of evidence.”[28]  Additionally, FDA has issued guidance regarding remote monitoring devices used to support patients during the pandemic.[29]  At least during this public health emergency, “FDA does not intend to object to limited modifications . . . [to] certain non-invasive remote monitoring devices.”[30]  Here, for example, modifications such as “[h]ardware or software changes to allow for increased remote monitoring capability,” will be permitted even without a 510(k) premarket notification.[31]

If this commitment to using RWE and expanding the use of telemedicine continues after the conclusion of the pandemic emergency, it would provide a huge advantage by having FDA’s decisions reflect current data and analyses, instead of sometimes being constrained by delays in data aggregation and analysis.

2021:  a slow return to “normalcy”

When the calendar turns to January 1, 2021, we will be hoping for a fresh start and a more hopeful outlook.  FDA will still be focused on addressing many pandemic-related issues, but there will eventually be a shift back to quasi-normalcy.  It is unclear whether FDA (or anyone for that matter) will return to a pre-pandemic normal, but we might start seeing FDA’s focus shift to more normal operations and its core mission. 

Given that FDA’s focus in 2020 was understandably dominated by its COVID response, large numbers of FDA personnel were taken away from their typical day-to-day activities.  As we settle into the “new normal,” those personnel will eventually be able to return to their usual functions.  Of course, we can expect to see the lessons learned during COVID—and many of the practices that were embraced by necessity—come to have a more lasting impact on how FDA and the regulated industries conduct business.  And, as we look back to evaluate the successes and missteps of the past year, FDA will undoubtedly adjust its strategic plans in preparation for any future pandemics.   

Even as COVID no longer dominates our dinner conversations, the lessons learned will serve us for decades to come.  FDA will be able to analyze mountains of data to determine which actions were successful and which need improvement.  If we encounter another pandemic—a scenario that is not unlikely—FDA will be able to improve and more swiftly tackle the pressing issues.  As we round the corner to 2021, we should look to the future with renewed confidence in both FDA and in our own abilities to confront the unknown.