The toolbox for treating COVID-19, hardly robust as is, became a little smaller thanks to an action today by the Food and Drug Administration. Hydroxychloroquine had received an emergency use authorization (EUA) in March after anecdotal data suggested therapeutic value in treating serious cases of the pandemic. Now that a clinical trial has shown no preventive benefit, and other data suggests no therapeutic benefit either, the FDA has pulled the EUA.
But did they act precipitately before — or are they acting precipitately now? After all, clinical studies on therapeutic use are still continuing, and this order does nothing to end them:
The Food and Drug Administration rescinded the emergency use authorization for hydroxychloroquine to treat hospitalized COVID-19 patients on Monday, saying the drug carries too many risks without any apparent benefit.
The authorization was first issued in March, and applied to patients hospitalized with the illness and those in clinical trials. In April, the FDA warned doctors against prescribing the drug to COVID-19 patients outside of those settings. Monday’s action will not affect clinical trials, which are expected to continue. …
“In light of ongoing serious cardiac adverse events and other serious side effects, the known and potential benefits” of hydroxychloroquine no longer outweigh those risks, the FDA wrote on its website Monday.
This seems like a curious step in light of the University of Minnesota clinical study, the results of which were released a couple of weeks ago. That study found no prophylactic value in taking hydroxychloroquine, either with or separate from zinc, which put a damper on its use as a treatment. That same clinical study, however, also found no dangerous side effects when prescribed for those without any contraindications for hydroxychloroquine.
So where is the FDA getting its information on “serious cardiac adverse events”? Hopefully not from the now-discredited Surgisphere “study,” which The Lancet and the New England Journal of Medicine belatedly withdrew. In fact, as John noted earlier, Surgisphere no longer exists at all.
The FDA says that the decision comes from data it got from a “a large, randomized clinical trial in hospitalized patients that found these medicines showed no benefit for decreasing the likelihood of death or speeding recovery.” Their letter and its addendum doesn’t give a lot of confidence in the need to withdraw the EUA from all therapeutic efforts, nor does it seem solid on the risk factors either. The study was limited to in-patient hospitalizations, not those managing acute infections outside of hospitals, and the conclusion seems rather weak in any case:
Only one study evaluated cardiac safety associated with HCQ treatment (Rosenberg et al31). This study was a retrospective multicenter cohort study of patients with laboratory-confirmed COVID-19 admitted to one of 25 participating New York metropolitan region hospitals. The primary effectiveness outcome was in-hospital mortality. After adjustment for demographic characteristics, hospital, preexisting conditions and illness severity, no significant differences in mortality were found between patients receiving HCQ + azithromycin, HCQ alone or azithromycin alone compared with neither drug. The secondary cardiac safety outcomes were cardiac arrest and abnormal ECG findings (based on chart review). Compared to patients who received neither HCQ nor azithromycin, risks of cardiac arrest were higher among patients receiving HCQ + azithromycin, and those receiving HCQ alone, although the risk estimates were not statistically significant for the monotherapy group. FDA reviewers concluded that this study is limited by potential for residual confounding and bias due to outcome misclassification, and overall, the available observational data are of insufficient quality to inform the effectiveness or safety of HCQ or CQ use in the COVID-19 population.
Surgisphere does make a brief appearance in the letter, mainly just to disassociate the FDA from its data:
In an Addendum included in the Memorandum, reviewers additionally evaluated a large observational study of HCQ and CQ with or without a macrolide for the treatment of patients hospitalized with COVID-19, based on data from a multinational registry (Mehra et al32). This publication was subsequently withdrawn by the authors33 and will not be included in this Memorandum.
The FDA may not have counted Surgisphere’s data, but it also doesn’t sound all that confident in the one study they do cite for cardiac risk. And again, that only applied to in-patient use of hydroxychloroquine. The original EUA didn’t only apply to inpatient use, and its withdrawal means that doctors can’t use it at the moment for outpatient use either.
That might end up being the right call, but we can’t know that until we see clinical data on outpatient use. In fact, it’s not even all that clear that we have solid knowledge on risks for inpatient use. Why not wait for the U of M study on therapeutic use to conclude? Hopefully we will start to see effective therapeutics that will eclipse hydroxycholoroquine anyway, but it still seems as though politics continues to drive both sides of the hydroxchloroquine question, even at the FDA.