Using its authority to approve treatments for emergency use, the Food and Drug Administration recently allowed convalescent plasma for hospitalized Covid-19 patients. But because the large 35,000-person study on the treatment lacked true randomization and placebos, we don’t really know if antibody-rich plasma actually improves mortality.
In fact, both Francis Collins, the director of the National Institutes of Health, and Anthony Fauci, the government’s top infectious disease expert, raised concerns that emerging data on the treatment was not strong enough to merit emergency approval.
Convalescent plasma illustrates more than a problem with the F.D.A.’s approval process. It points to a larger shortcoming in clinical research in the United States.
Americans and American biomedical researchers have often prided themselves on conducting the best clinical research in the world. Yet with over six million Covid-19 cases and almost 183,00 deaths, the United States has produced little pathbreaking clinical research on treatments to reduce cases, hospitalizations and deaths. Even one of the most important U.S. studies to date, which showed that the antiviral drug remdesivir could reduce the time Covid-19 patients spent in the hospital to 11 days from about 15, had too few patients to demonstrate a statistically significant reduction in mortality.
Progress on therapeutics research has been a very different story in Britain. In mid-March researchers there began a randomized evaluation of Covid-19 therapies, known as Recovery, that involves every hospital in the nation. The goal was to conduct large, rapid and simple randomized trials to define standard treatment. Some 12,000 patients were quickly randomized — the process of assigning them by chance to receive different treatments — and within 100 days of the effort’s start, researchers made three major discoveries that transformed Covid-19 care worldwide.
Researchers found no benefits from the use of hydroxychloroquine in hospitalized Covid-19 patients. Nor did the lopinavir-ritonavir drug combination benefit patients. On the other hand, dexamethasone, an inexpensive steroid, was found to reduce mortality by up to one-third in hospitalized patients with severe respiratory complications. Each of these results was conclusive and went against the expectations of many clinicians, guideline writers and lay advocates. The results demonstrated the critical need for randomized trials to separate out drugs we hope work from treatments we know work.
In the United States, by comparison, the government-sponsored Patient-Centered Outcomes Research Institute has spent millions of dollars creating a large clinical research network but has produced no research results on Covid-19 therapeutics.
That’s not to say nothing has been done. In April, the institute did begin HERO, an effort to bring together health care workers to share their clinical experiences, and a randomized trial to determine whether hydroxychloroquine can prevent coronavirus infections. But so far, that trial has enrolled only 10 percent of the health care workers necessary for the trial and as a result has reduced its enrollment targets; no useful results are likely. Only at end of July did Dr. Collins finally announce that the National Institutes of Health was preparing to begin large-scale clinical trials for Covid-19 treatments. And it wasn’t until last month that the N.I.H. began two trials to test antibody treatments.
But with about 1,000 Americans and more than 5,000 others worldwide dying every day from Covid-19, taking until the end of July to begin enrolling patients in randomized trials seems a bit slow.
As the United States designs research protocols to investigate clinical therapeutics, we should ask: What has gone right in Britain that the United States can adopt to help rapidly and definitively identify Covid-19 therapeutics that really work, and just as important, those that don’t?
Maybe the most important factor is an attitudinal difference: British clinical researchers have a longstanding commitment to large, simple and rapid randomized trials. American researchers prefer smaller, selective and complex trials with many restrictions on patients who can enroll.
Martin Landray, who is leading Britain’s effort, known as Recovery, identified six other factors that contributed to its success in an interview with us. They should be applied in the United States to produce more rapid, large-scale clinical trials of Covid-19 therapeutics.
First, the protocol for the Recovery trials was designed to be highly accessible, and the paperwork was short and easy for all health care providers — doctors, nurses, even medical students — to follow.
Second, the Recovery protocol was quickly approved at the national level and adopted by all hospitals in Britain.
Third, background patient data provided by Britain’s National Health Service helped to simplify the research process. Information like age, race and comorbidities are already built into the hospital systems for all patients, so providers didn’t have to collect that information. Follow-up data is more comprehensive because post-discharge mortality can be tracked through the N.H.S. database.
Fourth, support from top leaders in government health care ensured widespread uptake by hospitals. The four chief medical officers of England, Scotland, Wales and Northern Ireland each wrote to every hospital executive in their country that participating in the Recovery trial was a priority.
Fifth, Britain has a national system of research nurses who were rapidly redeployed to work on Covid-19 research at the beginning of the pandemic.
And last, the British effort was incorporated as part of everyday clinical care in hospitals. The alternative, of just trying anything and everything in a haphazard manner, which seems to have been the American way, was rejected in Britain because it neither optimizes patient care nor generates useful data. The philosophy that clinical research is the standard of care — a philosophy common in cancer care — was the right and ethical approach for Covid-19
An additional feature worth noting about the Recovery trial is that it has been relatively inexpensive to conduct. Oxford’s grant for the study was roughly $2.1 million. N.H.S. clinicians recruited patients as part of their job and drugs were provided as part of the N.H.S. Even with the additional cost of paying for clinical research associates, the trial was remarkably inexpensive and has proved its value.
What Britain succeeded in doing is not beyond U.S. capabilities. America has health networks with comprehensive patient data on a meaningfully large scale. Though networks don’t encapsulate the full U.S. population, they cover enough patients to provide background data for large clinical trials.
Moreover, the United States has no shortage of researchers, who can be deployed on Covid-19 therapeutic research, especially as many have been freed up with other research having been put on hold.
Unfortunately, unlike Britain, the United States has lacked a clear, unified message from government health care leaders, major insurance companies and hospital systems to put in place large, simple randomized trials that are considered the standard of care for Covid-19 treatment. We need to change that muddled approach now and reassert the nation’s clinical research excellence.
Ezekiel J. Emanuel is vice provost of global initiatives and professor of medical ethics and health policy at the University of Pennsylvania. Cathy Zhang and Amaya Diana are researchers in the department of medical ethics and health policy at the university.
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