On March 28, the Food and Drug Administration approved the emergency use of the antimalarial drugs chloroquine phosphate and hydroxychloroquine sulfate for hospitalized Covid-19 patients. This decision was partly based on early, but limited, data on their effectiveness. The FDA, however, stipulated that emergency use is authorized only when clinical trials aren’t available or participation isn’t feasible. This stipulation highlights the importance of properly conducting well-designed clinical trials without interference. These trials demonstrate the safety of a novel therapy and then, through a randomized controlled trial (RCT), can prove that a novel therapy works. This reflects the standard process of authorization for emergency use of unapproved therapies.
Initially, clinical trials must show that medications are safe in healthy adults and then in affected patients. Malaria drugs are known to cause complications in some adults taking them for malaria or autoimmune diseases; these complications aren’t common to all patients. We don’t know what complications may arise from using these medications in Covid-19 patients, or for which patients. No published stories have appeared about these drugs causing harmful effects in Covid-19 patients, but it’s possible that too few patients have been treated to see such complications. The safety of these drugs, given the projected number of patients, needs further investigation.
In addition to safety investigations, we need to complete RCTs to assess whether the drugs actually work. According to the Centers for Disease Control, most people with Covid-19 infection recover. This is true even for those patients admitted to the hospital for respiratory symptoms. Any novel therapy used to treat a patient with mild or even moderately severe Covid-19 will, at first glance, look like it improved the clinical outcome. In order to know if the antimalarial drugs work, we must compare the clinical response of these medications to the current standard therapy—that is, supportive care such as supplemental oxygen, mechanical ventilatory support, IV fluids, and antibiotics; or, alternatively, no treatment. The comparison group of patients not getting the drugs is the control group; the group receiving the drugs is the treatment group.
Well-designed and well-implemented RCTs contain many important elements, but I want to highlight three. First, it’s important that the RCT be explicit about which disease or subset of disease the novel therapy hopes to help. In the case of Covid-19, it’s essential to examine whether the research was focused on asymptomatic patients, hospitalized patients, and/or ICU patients to determine what level of disease severity would benefit from these medications. If the patient profiles include more than one important subtype, it’s difficult to discern quickly for which group the medications worked, for which the medications didn’t work, and/or for which the medications made the patients’ condition worse. One shouldn’t take information gathered from one subset of patients and assume it applies to other subsets of patients. This is especially important when confronting the pressure of fast-tracking a medication because of a pandemic.
Second, the investigative team must actively assign participants in the RCT to either the treatment group or the control group. The assignment can’t be made by patients or their medical providers. It’s possible that the patient’s or the provider’s decision to use the novel therapy could be heavily influenced by the presence (or absence) of factors that themselves affect the outcome (such as age, severity of illness, or other underlying medical conditions). If such patients show clinical improvement after using the novel therapy, it’s hard to tell what caused the improvement.
A third important element is random assignment. Factors besides the novel therapy may affect clinical outcomes, so we want to ensure that those assigned to receive the novel therapy look exactly like those assigned to the control group. The only way to ensure that other factors potentially influencing outcomes are the same in each group is to assign patients to each group randomly. In this instance, each patient’s assignment is determined by a coin flip. We know that if only a few flips are made, then the number of times the coin comes out heads, for example, can exceed the number that it comes out tails; if the coin is flipped enough, however, the number of times it comes up tails will equal the number of times it comes up heads. In the case of an RCT, if enough patients are enrolled and the assignments are random, patients assigned to the treatment group should ultimately look similar to the patients assigned to the control group—making it possible to determine that any difference in benefits comes from the novel therapy.
The French- and Chinese-published studies of antimalarial drugs for the treatment of hospitalized patients have their limitations, from a lack of random assignment to a small number of patients enrolled. We still don’t know whether the drugs are better than the current standard of care or whether they may be harmful in Covid-19 patients—thus confirming the necessity of conducting safety tests and larger RCTs with these drugs and showing why the FDA and health-care providers wish to withhold emergency treatment with unproven malaria medications in order to protect the ability to enroll people in clinical trials. This is why the FDA approval for emergency use of the drugs stipulates that their use is authorized only when clinical trials aren’t available, or participation isn’t feasible.
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