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The Need for a US National Clinical Trial Infrastructure in a Public Health Crisis

Scott Gottlieb, M.D.

When a small retrospective, observational study1 was recently published that suggested that use of the drug hydroxychloroquine together with high doses of the antibiotic azithromycin might have a beneficial treatment effect on a subset of critically ill patients with COVID-19, longtime proponents of hydroxychloroquine hailed the results as validation that they were right about the drug all along. By this point, hundreds of studies, many of which were rigorous, prospectively randomized and controlled trials, had firmly debunked any role for hydroxychloroquine in the treatment or prevention of COVID-19.2,3

This preponderance of evidence against hydroxychloroquine did not matter. News commentators and political figures who had promoted the drug touted the new study as proof that their advocacy was right.4 The orthodoxy around the drug’s purported benefits was firmly planted. The results were quickly seized to support this preferred narrative.

The US response to COVID-19 suffered from our inability to quickly enroll and complete rigorous studies that could provide more definitive evidence around not only which treatments worked to reduce the symptoms and severity of COVID-19, but also decisively establish which drugs were not effective. In the absence of conclusive information, findings from speculative studies, observational data, and anecdotes were able to fill the ensuing information vacuum. A devotion was able to form around the hoped-for benefits of drugs like hydroxychloroquine and, once established, that belief was impossible to pierce—even when more decisive evidence eventually emerged, much later in the crisis.

Too much of the early research undertaken during the pandemic came in the form of poorly designed observational studies or other constructs that were never going to yield clear, actionable results. The research community missed an opportunity early on to field the kinds of practical studies that could be quickly completed in the setting of a crisis but still generate firm evidence that would form the basis of properly informed treatment decisions. An analysis done by Janet Woodcock, MD, who headed the Center for Drug Evaluation and Research at the Food and Drug Administration (FDA) and had served as the therapeutics lead for Operation Warp Speed (and is currently the agency’s acting commissioner) found that more than 90% of the clinical trials underway that evaluated different medicines for the treatment of COVID-19 were designed in a fashion that would never enable the studies to yield firm results that could reliably shape the practice of medicine.5

The US has a distributed system for the conduct of clinical research in which investigators are able to pursue studies without much central coordination. Although a lot of research is sponsored by federal and state agencies, as well as professional societies, much of the work is investigator-led. In normal times, this decentralized process serves science well. It allows individual researchers to pursue the questions they find most pertinent and creates a competitive market for ideas and science that advances the field of medicine. But in a crisis, resources for conducting research are scarce. Clinicians do not have time to run multiple, rigorous studies, and enrolling patients in a setting where clinicians are delivering emergency care can be difficult. When COVID-19 struck, the uncoordinated system for clinical research meant that many of the most important clinical questions did not get addressed in a timely manner.

In some cases, such as the episode involving hydroxychloroquine, the US spent too much time conducting multiple studies to investigate questions that should have been more firmly answered earlier during the pandemic. But addressing them would have required the federal government to coordinate the execution of definitive studies from the very outset. What was needed was the opportunity to direct the completion of large, practical studies that are easier to initiate in the setting of a crisis yet still likely to yield both timelier and rigorous answers to key challenges.

British researchers proved through the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial the value of having more central organization around the conduct of research in the setting of a public health crisis, as well as the virtue of practical trial designs that can be more easily enrolled and completed in the setting of an emergency.6 In the US, a similar authority was needed to steer enrollment into a large, practical trial like RECOVERY that would help establish which treatments were providing benefit and which ones offered no advantage. The US did not participate in RECOVERY, deeming it to be insufficiently rigorous. Yet many of the most important clinical results came from that single trial, such as evidence supporting the use of dexamethasone in the treatment of hospitalized patients with COVID-19.7

The US needs a coordinated national clinical trial infrastructure in the setting of a public health crisis. Instead, during COVID-19, US investigators conducted hundreds of scattered trials that were, in many cases, poorly designed, and would never yield practical evidence.8 At the same time, we were not able to establish early enough when treatments that were in widespread use were not providing patients with any benefit and were perhaps causing harm.

To prepare for the next pandemic, the US should empower the FDA and the National Institutes of Health (NIH) to steer patients into trials that are more likely to yield actionable evidence that can inform clinical practice and improve outcomes. That also means that we need to rely more on practical trial designs such as the approach used in the RECOVERY trial. The FDA and the NIH should have the authority to prioritize among therapies those that have the most promise and accelerate enrollment of studies to evaluate these high-priority medicines.

In June 2020, the FDA revoked its authorization for the emergency use of hydroxychloroquine after the agency had determined that the drug was unlikely to be effective.9,10 Around the same time, the NIH stopped its single definitive trial examining the drug’s use after interim data showed that it provided no benefit compared with a placebo. But a sizable number of individuals in the US continue to believe that hydroxychloroquine is effective for COVID-19 because its use—and the lore surrounding the drug—persisted for too long. As a result, even after definitive evidence finally emerged to debunk its purported benefits, those belated facts and firm science do not prevail.

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