Publishing During the COVID-19 Epidemic: Prompt Conclusions or Quality Studies?
FOR COMPREHENSIVE COVID-19 ETHICS AND POLICY RESOURCES, VISIT OUR DEDICATED WEBPAGE, BIOETHICS.JHU.EDU/CORONAVIRUS.
By Michael Erdek, MD, MA
Johns Hopkins Berman Institute of Bioethics and School of Medicine
The current COVID-19 health crisis warrants dissemination of outcomes from clinical trials in a relatively prompt fashion given the steep slope of the infection curve and the concomitant dire predictions regarding both patient care and resource utilization. It thus stands to reason that researchers are motivated to turn around data rapidly, consistent with serving the common good in time of extreme need. This process, however, has its limits when underpowered studies with limited data yield conclusions with broad-reaching implications.
There is little doubt that an urgent need for treatment of SARS-CoV-2 exists. But premature publication of definitive recommendations based on inappropriate conclusions grounded in scant, hastily-acquired data serve only at best to confuse and at worst mislead at a time when tensions are high and need for help is great. One recent study by Gautret etal., “Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open label non-randomized clinical trial,” published in the International Journal of Antimicrobial Agents and receiving attention all the way to the White House, raises such concerns.
In this investigation, 36 SARS-Co-V-2 positive adult patients were studied over a two-week period at a hospital in Marseille, France. Twenty patients received 200 mg of hydroxychloroquine sulfate three times per day for 10 days while 16 patients served as control subjects. Six of those randomized to the active treatment also received 500 mg of azithromycin on Day 1 and then subsequently 250 mg per day for four additional days at the authors’ discretion “depending on clinical presentation” in order “to prevent bacterial superinfection.”
The results detail that at Day 6, 100% of those treated with combination hydroxychloroquine and azithromycin demonstrated virological cure (per negative nasopharyngeal PCR results), compared with 57.1% of those receiving hydroxychloroquine only and 12.5% in the control group (p<0.001). The recommendation issued by the authors was thus that “COVID-19 patients be treated with hydroxychloroquine and azithromycin.”
Publication of recommendations based on studies such as this is highly problematic. An investigation with only 20 treated patients (after six dropped out due to cessation of therapy) is significantly underpowered and greatly subject to sample size error. Further, the reason for the addition of azithromycin is poorly described and subject to question. It is one thing to call results promising, it is another to issue definitive treatment recommendations. Hydroxychloroquine exists in limited supply, and poorly grounded recommendations touting effectiveness by health care providers and/or President Trump who touted it last week as “a game-changer” that has shown “very, very encouraging results,” only exacerbate this shortfall without correlative evidence of demonstrable benefit. This is even more troubling with regard to azithromycin, where overuse may lead to resultant potential shortages of an important antibiotic needed to treat bacterial infection as well as the downstream effect of increasing the number of strains of drug-resistant pathogens.
It is ironic that the authors of this study state, “For ethical reasons and because our first results are so significant and evident we decide to share our findings with the medical community, given the urgent need for an effective drug against SARS-CoV-2 in the current pandemic context.” The true ethical responsibility of researchers is to produce and to publish data and subsequent recommendations yielded as a function of robust methodology and stringent review. Perhaps some investigators may be altruistically motivated in an effort to rapidly disseminate hopeful conclusions. Nevertheless, the responsibility we hold to our patients and, especially in the setting of the current pandemic, to greater society at large depends on good judgment and fiduciary concern rather than on haste to demonstrate beneficial outcomes.