Trials and Therapeutics: Important Lessons from the COVID-19 Pandemic

Efeose (Efe) A. Airewele and Rajesh T. Gandhi

Abstract

In 2020, the COVID-19 pandemic gripped the world, and clinicians scrambled to find effective treatments for their patients. Through unprecedented rates of research and collaboration across disciplines, several therapies were demonstrated to show promise, while others fell short. In this piece, we argue clinical trials can—and, indeed, must—be done during a pandemic to identify safe and effective therapeutics and that these trials must be completed free of political pressures. For optimal treatments, we ought to prepare clinical trials before—not during—public health emergencies.

Politics & the Pandemic

In August 2020, convalescent plasma (CP) results quickly turned political during the COVID-19 pandemic. Some officials claimed that CP treatment was more effective than it was, and there were concerns that there were political pressures on the Food and Drug Administration (FDA) to issue an Emergency Use Authorization (EUA) prematurely.

EUAs were developed as a response to the growing threat of bioterrorism after the September 11^th and anthrax postal attacks in 2001.¹ Congress permitted the FDA to authorize unapproved products for use against potential dangers that threaten public health and safety. However, in the previous decade, its use has been relatively limited, with the most extensive use during the 2009 H1N1 pandemic. The current public health emergency has seen unprecedented numbers of EUAs which have allowed timely access to potentially effective treatments. However, these EUAs are not intended to serve as recommendations for clinicians because the “may be effective” criterion for an EUA is different than guidance on optimal patient care.

In the COVID-19 pandemic, guidelines panels of the National Institutes of Health (NIH) and Infectious Diseases Society of America (IDSA) weighed the risks and benefits of treatments based on available data to make recommendations to clinicians on how to care for their patients. These guidelines and EUAs do not always align, which was the case for CP when guidelines panels maintained that “there are insufficient data … to recommend either for or against the use of COVID-19 convalescent plasma for the treatment of COVID-19.”² Recently, a trial in hospitalized patients found that there was no demonstrated clinical benefit for those treated with convalescent plasma.³ Although CP is still being studied, there is currently no definitive evidence for its use in hospitalized patients. This example illustrates the need to complete clinical trials before a therapy is adopted.

Recap of Notable COVID-19 Treatments

In March 2020, COVID-19 was officially declared a pandemic by the World Health Organization (WHO), and shortly after the United States declared a national emergency. At the time, there was no known effective treatment for COVID-19, and the central component of therapy was supportive care. Without a vaccine or specifically designed antivirals, research was accelerated in search of effective treatments. A year later, although more research is still needed, the available data for COVID-19 therapeutics have grown immensely. Through various randomized controlled studies, researchers have concluded that certain therapeutics confer benefit while others fall short in demonstrating efficacy in treating COVID-19.

Early on in the pandemic, hydroxychloroquine was proposed as a potential COVID-19 therapy.⁴ Using the limited available data at the time, the Food and Drug Administration issued an EUA for hydroxychloroquine use in hospitalized patients in late March 2020.⁵ However, several studies later demonstrated that hydroxychloroquine showed no benefit in hospitalized patients⁶ and the FDA’s EUA was revoked. Subsequently, randomized controlled trials demonstrated that hydroxychloroquine was not effective as a post-exposure prophylaxis⁷ nor as a treatment for non-hospitalized adults.⁸ Additionally, trials showed a number of other treatments did not have clinical benefit. For example, trials found that lopinavir/ritonavir, which has a role in treating Middle East Respiratory Syndrome (MERS), does not demonstrate a clinical benefit for those with COVID-19.⁹

As the pandemic raged on, remdesivir emerged as the first antiviral drug to demonstrate a clinical benefit for COVID-19 inpatients. Compared to placebo, remdesivir significantly shortened recovery time for hospitalized adults.¹⁰ These data supported the May 2020 EUA issued for remdesivir use for hospitalized patients.¹¹ However, remdesivir treatment did not demonstrate a mortality benefit, highlighting the need for better medications.

In June 2020, dexamethasone was found to reduce mortality¹² in hospitalized patients with COVID-19 who required oxygen supplementation—the first treatment to improve survival. Subsequently, tocilizumab in combination with dexamethasone has been recommended for select patients who are hospitalized with progressive and worsening COVID-19.¹³ Baricitinib, in combination with remdesivir is also sometimes used to treat hospitalized patients with COVID-19.¹⁴

While remdesivir, dexamethasone, baricitinib (with remdesivir) and tocilizumab are used in hospitalized patients, anti-SARS-CoV-2 monoclonal antibody treatment has been found to benefit outpatients with mild to moderate COVID-19 who are at high risk for clinical worsening. These monoclonal antibodies have not yet been shown to help patients hospitalized for severe COVID-19, perhaps because viral replication is less prominent in this phase of the infection (see Figure 1). Despite the promising results of antibody therapy, rapidly evolving variants of the SARS-CoV-2 virus threaten future efficacy, and new treatments—including oral agents—are needed.

COVID-19 Treatment: No One Size Fits All

While researchers continue to identify potential new treatments, clinicians must use the currently available data when caring for their patients. Current epidemiological estimates indicate that most people with symptomatic SARS-CoV-2 infection will have mild to moderate disease and will not end up hospitalized.¹⁵ The outpatient management of these individuals is largely centered around the clinical goal of preventing disease progression and hospitalization. On the other hand, the inpatient management of patients aims to hasten recovery and prevent further complications and death. Depending on the phase and severity of illness, treatments will vary (see Figure 1).

Based on the current understanding of SARS-CoV-2 activity, antiviral treatment is most likely to be beneficial early in the disease when viral replication is active. These treatments may target the viral copying enzymes, like remdesivir, or neutralize the virus, like convalescent plasma and monoclonal antibodies. By contrast, anti-inflammatory medications, like dexamethasone, tocilizumab, or baricitinib, are most relevant later in disease progression, such as in hospitalized patients, when excess inflammation is driving the disease course.

Lessons Learned

As the list of effective (and ineffective) COVID-19 therapeutics grows, we can learn from the scientific processes that lead us here. The initial use of ineffective drugs like hydroxychloroquine was, in part, spurred by early observational studies.¹⁶ However, observational studies have significant limitations due to the lack of a control group. The ensuing confounding variables may lead to incorrect conclusions. Consequently, although well designed observational trials play a role in the development of evidence-based medicine, they can be misleading.

The limitations of observational data are well known to the clinical research community. For example, observational data suggested estrogen replacement therapy in postmenopausal women may reduce the risk of cardiovascular disease. These observational data guided clinical practice for years until a randomized controlled trial demonstrated hormone replacement therapy was actually associated with an increase in cardiovascular disease.¹⁷ In this example, the observational data may have been confounded by differences in health-seeking behavior by women who did or did not receive hormonal replacement; it was only randomized trials that led to definitive conclusions. As we continue to combat the current public health emergency, it is of the upmost importance to apply previously learned lessons to ensure that the development of therapeutics involves robust randomized controlled trials.

The past year has emphasized the need to conduct clinical trials to find effective treatments free of political pressures. We have learned that we can—indeed, must—do clinical trials during a pandemic to find out what does and does not work. Another critical lesson of COVID-19 is that we need to prepare for pandemics, including setting up adequate clinical trials infrastructure before we are in a pandemic rather than during a public health emergency when clinicians are in the midst of caring for many critically ill patients. These preparations will serve us well in ending the current COVID-19 pandemic and responding more rapidly to future healthcare emergencies.

Figure 1: Conceptual model summarizing key considerations for selecting potential COVID-19 treatments

About the Authors

Efeose (Efe) A. Airewele, B.S. is a recent graduate of Cornell University and is currently the Clinical Education Assistant in the Infectious Disease Division at Massachusetts General Hospital. She has a background in global and public health and is interested in infectious diseases, particularly how they disproportionately impact communities of color. She can be reached at efe.airewele@gmail.com.

Rajesh T. Gandhi, M.D. is Professor of Medicine at Harvard Medical School and the Director of HIV Clinical Services and Education at Massachusetts General Hospital. He is also the Co-Director of the Harvard University Center for AIDS Research. Dr. Gandhi is a member of the NIH Covid-19 Treatment Guidelines Panel and the Infectious Diseases Society of America Covid-19 Treatment Guidelines Panel. He can be reached at rgandhi@mgh.harvard.edu.

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