Reply.

To the Editor:

We thank Dr. Tang and colleagues for their interest in our study and for their correspondence on an important clinical question. In May of 2020, when our literature search was last updated, we did not identify any case series, cohort studies, or randomized controlled trials (RCTs) that evaluated the role of HCQ as prophylaxis for COVID‐19. Consequently, our analysis was unable to address this issue. The authors should be commended for their efforts to conduct an RCT during the early phases of the pandemic when there was widespread misinformation about antimalarials. We empathize with the difficulties they encountered, which highlight broader issues impacting the COVID‐19 research agenda.

As noted in our analysis, early observational studies frequently had a high risk of bias, which could be attributed to small sample sizes, inappropriate or inadequate comparator groups, and issues related to confounding by indication. Over‐interpretation of the preliminary evidence led to off‐label HCQ use months before the first randomized trial was finished. An “infodemic” began, fueled by anecdotal reports of encouraging benefits and concerning harms (1). A seemingly contradictory situation arose, in which enrollment slowed because of overconfidence in HCQ’s purported benefit, and trials were paused or terminated in response to potential safety signals. The typical regulatory and logistic hurdles to initiating RCTs compounded delays, resulting in many RCTs beginning after COVID‐19 peaks had passed. Perhaps most importantly, aside from notable exceptions like the RECOVERY trials, few large‐scale coordinated RCTs of HCQ were performed (2).

The importance of conducting large‐scale, adequately powered RCTs and the consequences of relying on suboptimal evidence when they are absent will be one of the enduring legacies of the COVID‐19 pandemic (3, 4). Performing such trials will require greater collaboration between centers and a regulatory environment that encourages their execution. It will also require investigators like Dr. Tang and colleagues, who were willing to expend time and effort in this worthy endeavor.

The views expressed here are those of the authors and participating members of the COVID‐19 Global Rheumatology Alliance and do not necessarily represent the views of the American College of Rheumatology, the European Alliance of Associations for Rheumatology (EULAR), or any other organization. Dr. Putman is recipient of a Scientist Development award from the Rheumatology Research Foundation. Dr. Sattui’s work was supported by the Vasculitis Clinical Research Consortium and by a Vasculitis Foundation fellowship award. Dr. Sparks’ work was supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Disease grants K23‐AR‐069688, R03‐AR‐075886, L30‐AR‐066953, P30‐AR‐070253, and P30‐AR‐072577), the Rheumatology Research Foundation R Bridge award, the Brigham Research Institute, and the R. Bruce and Joan M. Mickey Research Scholar Fund. Dr. Duarte‐García’s work was supported by the CDC (grant U01‐U01DP006491), the Rheumatology Research Foundation Scientist Development award, the Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, the Women's Health Career Enhancement award, and the Eaton Family Career Development award. Dr. Sparks has received consulting fees, speaking fees, and/or honoraria from Bristol Myers Squibb, Gilead, Inova, Janssen, and Optum (less than $10,000 each) and research grants from Bristol Myers Squibb and Amgen. Dr. Liew has received research support from Pfizer.