The World Health Organization recently paused — and then restarted — its COVID-19 hydroxychloroquine coronavirus clinical trial over safety concerns. The pause came in the wake of two large reviews of data from patients who received hydroxychloroquine that reported generally negative results.
The Lancet, the journal that published one of these studies, recently retracted it due to concerns about its credibility. This came in the wake of two large reviews of data from patients who received hydroxychloroquine that reported generally negative results.
The failure to reach a decisive answer about hydroxychloroquine highlights that the best way to definitively determine if a medication is truly safe and effective for treating COVID-19 is through clinical trials, the gold standard of medical research. A clinical trial involving the administration of a research medication in a controlled setting with comparison groups is the best way to learn if a medication is effective, ineffective, or even harmful.
It would not be surprising if some of the ongoing trials evaluating hydroxychloroquine reveal that it fails to safely treat COVID-19. More than 90% of medications don’t work as hoped when tested in good clinical trials. The real tragedy here is that tens of thousands of patients have already received this medication outside of a formal clinical trial because the usual and most responsible process was short cut.
Hydroxychloroquine is an example of the hazards of using unproven medications. Even though it has been effective against coronavirus in the test tube and in some small clinical studies, experts have been pessimistic about treating COVID-19 with it. The few studies that have shown a benefit to date were small and not well conducted.
Hydroxychloroquine had one very important thing going for it — its support and use by President Donald Trump. Once this became known, this relatively obscure medication instantly became a political issue. In March, the Food and Drug Administration granted hydroxychloroquine an Emergency Use Authorization (EUA), a mechanism designed to make a medication available in the event of a public health emergency even without clinical trial data supporting its safety and efficacy. This declaration also allowed the release of hydroxychloroquine from the Strategic National Stockpile, an emergency repository of medical supplies. This week, the FDA revoked the EUA based on emerging information.
Prior to the EUA, hydroxychloroquine was already legally prescribed for COVID-19 by many clinicians. Hydroxychloroquine is FDA-approved for treating diseases such as malaria and rheumatoid arthritis, so clinicians can prescribe it as they choose. This practice is known as “off-label use.” Under U.S. law it is permissible for clinicians to prescribe any FDA-approved medication for any indication that they believe would benefit their patient. Off-label prescribing is an accepted and common practice because it isn’t simply practical to obtain FDA approval for every possible condition where a particular medication may be helpful.
The EUA seemed to validate hopes that hydroxychloroquine is helpful against COVID-19 and more clinicians began prescribing it to sick patients. Even more concerning, some healthy people hoarded the medication in case they were exposed or infected. These practices caused shortages, and patients who had been taking hydroxychloroquine for years for rheumatoid arthritis were unable to fill their prescriptions.
As if these drug shortages weren’t bad enough, perhaps the biggest problem with off-label use of hydroxychloroquine for COVID-19 was that it became hard to see that the medication wasn’t working. COVID-19 mortality hovers around 1% overall with standard treatment. How would an individual clinician ever tell if an investigational drug was 50% worse (mortality 1.5%) from treating only a handful of patients?
Clinical research, regulated by the federal government, has ethics board oversight, formal protocols, and prospective data collection to ensure that participants are treated safely and selected fairly. Research uses an informed consent process to help ensure patients understand the risks of participating. One of the risks is that taking an unproven medication may prevent participating in the study of another medication, which may be more promising. Indeed, some of our patients who were taking hydroxychloroquine for COVID-19 outside of a research study were surprised to learn that the medication was unproven, and that receiving it made them ineligible to participate in some clinical trials of other investigational medications.
We often hear people ask, “What do I have to lose?” when considering an unproven drug for a disease without good treatments. As in the case of hydroxychloroquine for treating COVID-19, the answer is a lot. Sometimes your life.
Andrew Stolbach (email@example.com) is an emergency physician and co-chair of a Johns Hopkins Institutional Review Board. Dr. Jeremy Sugarman (firstname.lastname@example.org) is a general internist and professor of Bioethics and Medicine at the Berman Institute of Bioethics.