Medical Editors Urge Cautious Interpretation of COVID-19 Clinical Trials

Anticipating that numerous randomized clinical trials (RCTs) of potential treatments for coronavirus 2019 (COVID-19) will release preliminary results and submit reports for peer-review publication in the coming weeks to months, executive editors at JAMA called for critical assessment and managed expectations.

Howard Bauchner, MD, and Phil Fonanarosa, MD, MBA applauded the clinical trials community and funding agencies for rapidly developing and conducting RCTs during the COVID-19 pandemic. In their editorial, they declare this effort "a remarkable achievement.”

They cautioned, however, that the results, albeit eagerly awaited, should not be accepted and conveyed without close scrutiny of the data and trial designs.

"Presenting and interpreting the results of these studies clearly, and communicating findings appropriately to clinicians, the public and policy makers is critically important," Bauchner and Fonanarosa warned. "Because much of the focus is now on preventing recurrence of the pandemic, it will be important for investigators, journals, and the media to accurately report the results of the studies responsibly and what they mean both for individuals and for population health."

Bauchner and Fonanarosa pointed out that the trials vary in their methodology and measures.

Some, but not all trials include control groups, and use a single agent rather than a combination. The trials also vary on clinical outcome measures and apply these at different levels of disease severity.

"Without rigorous design and attention to trial protocols for study drug administration, there will be challenges disentangling the true effect of the intervention,” they wrote.

The editors also pointed out that much has been learned about the disease since many of the trials were designed. For example, it is now apparent that patients with severe COVID-19 can present with a range of conditions besides severe hypoxia, including inflammatory activation and coagulopathy.

"Accordingly, there may be significant heterogeneity of treatment effects based on the timing or constellation of disease manifestations," they indicated.

The trials are also unlikely to be sufficiently powered to ascertain whether the interventions reduce mortality, Bauchner and Fonanarosa noted. Further, even highly successful trials with a minimum 10-20 subjects are unlikely to show more than 5% to 10% absolute difference in mortality; and a study with smaller absolute difference would require a larger cohort.

"This remains a challenging issue for clinicians and patients to understand," they wrote. "Give these likely numbers needed to treat, most patients will not benefit from even a successful treatment."

Bauchner and Fonanarosa also noted that most of the upcoming trials are directed at treatment, with fewer examining new measures for containing and preventing the spread of SARS-CoV-2.

"The results of these trials—most of which are being conducted among hospitalized patients in whom the disease is well-established—might not necessarily be directly applicable for altering the incidence of disease in the coming months or preventing future surges of disease," they noted.

Bauchner and Fonanarosa are hopeful, however, that the findings from rigorous clinical trials of vaccines and other possible interventions will yield the means to effectively prevent COVID-19.

They also indicated that they would hope to see data being shared between similar trials.

"The goal is to expand what is known about possible treatments, so that future trials can be improved, perhaps by using approaches such as large adaptive platform trials," they proposed.