I repeat, hydroxychloroquine doesn’t work (for now)

Why the drug is unlikely to be beneficial to Covid-19 patients and could carry potential risks

Game changer! The missing ingredient! No more lockdowns needed! These headlines scream for attention from newspapers and webpages on a regular basis. Some people share them, and some go viral. While most are eventually debunked and lose steam, a few develop a life of their own and continue to resurface even after repeated explanations from health authorities and science experts.

Part of the problem is that people can misunderstand how science works. Science is a messy process with a hierarchy of proof. Evidence for efficacy builds from the study before it. The smaller, older studies become the basis for the performance of bigger, newer, more extensive studies. If at any point the bigger study fails, then the smaller studies are not enough to overturn the findings of the bigger study since the bigger studies are typically better designed. The bigger studies are less likely to be biased or confounded by extraneous factors.

Drug development research goes through multiple stages. First come in-vitro or laboratory studies, and animal studies. Then studies on humans are done. Phase one studies test safety. Phase two studies look for the best dose while continuing to look at safety. Phase three studies are the randomized controlled trials (RCTs), which prove safety and efficacy. Phase four is a post-approval study, which continues to look for safety issues as the drug is used in clinical practice.

If a drug fails at phase one, there won’t be a phase two unless a revised phase one shows safety. Some evidence of efficacy in phase two will not be able to overturn lack of efficacy in phase three, because phase two isn’t designed to measure efficacy properly. If there is doubt about a negative finding from a phase three, then a new phase three can be done with different parameters.

Outside this formal framework, some drugs in emergency situations can be used “off-label” for compassionate use. “Off-label use” is when there is some evidence that a drug has a positive effect and is reasonably safe based on use for other diseases, and the doctor wants to try it for his very sick patient. As long as the patient understands the risks and benefits of treatment and consents to its use while accepting the risk, then the drug can be used carefully. Efficacy data in these instances can be highly biased as there is no proper comparison with a similar patient not taking the drug. It is possible that someone would have gotten better without the drug, but since the drug was given, any recovery will likely be attributed to the use of the drug. This kind of evidence for efficacy is called “anecdotal” evidence, since we recognize that there are other things that may have contributed to the patient’s recovery. The drug may not have had any effect and the recovery of the patient may just have been coincidental.

In the case of hydroxychloroquine and chloroquine, the initial evidence for use came from in-vitro experiments. These experiments showed that hydroxychloroquine was able to affect the reproduction of SARS-CoV-2 in cultured cells in a variety of ways. When Covid-19 first hit, this data became the basis for further studying the effect of the drug.

Since the situation was evolving, several countries including the Us allowed compassionate use of hydroxychloroquine based on two reasons. First, hydroxychloroquine is a reasonably safe drug that is used for conditions such as lupus and malaria. Second, there is some scientific plausibility it might work based on the in-vitro studies.

Doctors continued to use hydroxychloroquine (and chloroquine) for treatment of Covid-19 while waiting for the results on concurrent clinical trials. Since hydroxychloroquine was already being used in humans for other diseases, the studies for treatment of Covid-19 jumped directly to phase three.

The non-RCT hydroxychloroquine trials included non-randomized case series, case-control studies, and cohort studies. The evidence that emerged from these early studies was mixed, but there was enough motivation for physicians to use them in the absence of anything better. As the RCTs started, hydroxychloroquine took a political life of its own. Touted by President Trump as “one of the biggest game changers in the history of medicine” despite warnings from infectious diseases expert Dr. Anthony Fauci, hydroxychloroquine flew off the shelves, sometimes causing a shortage of the drug for patients who needed it for lupus. As more RCT data accumulated, it became apparent that hydroxychloroquine was not only ineffective, but came with significant side effects, especially when combined with the antibiotic azithromycin. WHO stopped its phase three trials, and the US FDA withdrew its emergency use authorization.

Without political interference, the scientific studies disproving the use of hydroxychloroquine would have been accepted by the medical community without fanfare. Doctors would have just continued investigating other drugs and treatments. Due to the polarization brought about by pundits touting its benefits, however, the push to keep using it for Covid-19 refused to die. To make things more confusing, doctors with large followings, including a renowned cancer epidemiologist from Yale University, opined that the studies that disproved its use were insufficient and flawed. While it is true that not all doses of hydroxychloroquine and chloroquine were investigated, the dosing regimens were based on best estimates of likely efficacy, given the proposed mechanism of action. There were also RCTs on severe disease, moderate disease, as well as post-exposure prophylaxis (taking the drug after a possible exposure) using lower than usual doses. All these studies showed no effect. There are also many RCTs with all sorts of dosing regimens and in combination with a multitude of interventions that are registered and enrolling. The data from these trials will help clarify and, with hope, put the matter to rest.

Enter a group of doctors who last week touted the benefits of hydroxychloroquine prophylaxis in the Philippines, calling an end to all lockdowns. To prove their point, they held an unauthorized mass gathering and shockingly refused to wear masks. They stated that they were all taking hydroxychloroquine and were therefore protected. When confronted by RCT evidence on the ineffectiveness of the drug, they produced a voluminous list of previous studies, none of which reached the standard of rigor required to refute the RCT data.

To be fair, it would be prudent to wait for the ongoing RCT studies before completely dismissing their claims. The act of not wearing their masks, however, shows that these doctors have clearly gone beyond the realm of science. Prudence demands that uncertainty be met with caution. By foregoing protective measures despite unproven protection, the doctors recklessly put themselves and all the attendees of their forum at risk for contracting Covid-19.

Former health secretary Jaime Galvez-Tan was among the group. He has since clarified that he does not believe hydroxychloroquine is effective as prophylaxis against Covid-19. He has also stated that he wore a mask through most of the event, except during his speech and while eating.

The preponderance of evidence for hydroxychloroquine shows it does not work. In science, the best way to disprove good evidence is to do a study and produce better evidence. More studies are coming, but in the meantime, we should not use hydroxychloroquine in any shape or form to prevent or treat Covid-19.