meAs a gigantic feat of scientific ambition, researchers have designed an astonishing 1,200 clinical trials intended to test Covid-19 prevention and treatment strategies since early January. But a new STAT analysis shows that the effort has been marked by disorder and disorganization, with huge financial resources wasted.
The analysis, carried out in collaboration with XL applied, a Newlab Venture Studio company, found that one in six trials was designed to study hydroxychloroquine or chloroquine anti-malaria drugs, which have been shown to have no benefit in hospitalized patients.
“If the goal was to optimize the likelihood of discovering the best treatment options, the system is out of the question,” said Robert Califf, head of clinical policy and strategy at Verily Life Sciences and Google Health and former commissioner of Food and Drug Administration . The results show, he said, that too often the studies are too small to answer questions, lack real control groups, and place too much emphasis on some potential treatments, such as hydroxychloroquine.
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In fact, the analysis found that many of the studies are so small (39% enroll or plan to enroll fewer than 100 patients) that they are unlikely to yield clear results. About 38% of the studies have actually not started recruiting patients.
“It is a lot of wasted effort and wasted energy when in fact a little coordination and collaboration could go a long way and answer some questions,” said Martin Landray, professor of medicine at Oxford University and one of the top researchers at the RECOVERY study, a great test of multiple treatments performed by the UK government.
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Not all effort has been in vain. So far, three of the most important conclusions about Covid-19 treatments come from the RECOVERY trial. Dexamethasone, an inexpensive steroid, has been shown to reduced the mortality rate of patients with Covid-19 in fans by a third. It has also been shown that neither hydroxychloroquine nor a pair of anti-HIV drugs, lopinavir and ritonavir, which had shown promise in laboratory models of the disease, benefit hospitalized patients with Covid-19.
Still, experts say the analysis shows that huge amounts of energy have been expended on casual efforts, often without a clear strategy to improve the odds that the results will actually inform patient care. Faced with intense pressure to develop drugs and vaccines at a previously unimaginable speed to roll back a global pandemic, researchers may have slowed the rate of progress.
For example, 237,000 volunteer patients were enrolled in hydroxychloroquine or chloroquine studies. That’s 35% of the 685,000 volunteer patients the researchers expected to enroll in any study. Since patients wishing to enter the studies are one of the scarce resources in medicine, this means that other potential treatments, such as ivermectin or favipiravir, were not studied.
That’s “excessive,” said Susan Desmond-Hellmann, former CEO of the Bill and Melinda Gates Foundation. She noted that vaccines, by contrast, are being developed in a more methodical way, and wished that research on new drugs had been more organized, rather than simply trying what was available.
Data for the new analysis comes from clinictrials.gov, the US government’s database.
AppliedXL analyzed the data to identify trials that explicitly studied Covid-19 therapies and prevention strategies. The analysis focused only on interventional clinical trials, which study possible or preventive treatments for the disease.. More than 880 observational studies have also been started, according to the analysis. For trials testing multiple treatments, all study enrollment for each drug was counted. (For more details on the methodology used in the analysis, see here).
The analysis reflects the data as of June 24. In the days leading up to the publication of this article, approximately 20 Covid-19 studies were added to the database each day.
The clinictrials.gov database is known to contain routine errors, oversights, and omissions, and industry and academic researchers often do not update trial lists. As a result, the analysis itself involved a certain degree of subjectivity. But the general conclusions, both on the scale of the research and on its limitations, seem indisputable.
Nahid Bhadelia, medical director of the Special Unit for Pathogens at Boston University School of Medicine, called the data “a clamor for greater global collaboration during pandemics.”
The United States’ research infrastructure was quickly mobilized when the pandemic began. In January, 10 studies would begin, followed by 43 in February and 99 in March. In April, according to the database, nearly 400 studies would begin for dozens of different treatments and preventives.
The great speed with which the studies began was remarkable. And experts said that starting some small studies, particularly of new and experimental drugs that were previously being tested in other diseases, makes sense as a way to find out what might work. But such “phase 1” studies accounted for only 12% of the total in the analysis.
Experts added that because the prognosis for Covid-19 patients varies so dramatically (some patients have no symptoms, while others die with ventilators), only large studies that randomly assign patients to a treatment or placebo They can give a real idea of whether the drugs are actually helping patients. Otherwise, the researchers are fooled into thinking that the differences between groups of patients with varying degrees of disease are caused by the drugs they are testing.
The RECOVERY study took a unique approach. To conduct such a large study, the researchers reduced the amount of data collected on each patient, focusing primarily on whether the patients lived or died, so that the front-line researchers can collect the data. More importantly, they obtained acceptance from the UK National Health Service that such a study was a priority.
Repeating that model, experts say, would teach doctors more about how to treat Covid-19, and it would do so much faster.
“If more people took the RECOVERY model, or something like that, they did it for the drugs they were interested in, in the patients they were interested in, in their part of the world … we progressed much, much faster,” he said. Landray.
Clinical trials can typically cost $ 10 million or more, and some studies cost hundreds of millions of dollars. But Landray says RECOVERY was funded by a grant of about $ 2.5 million to the center coordinating the study, although costs at the hospitals could raise the total.
In fact, of 1,200 studies, almost all of the true knowledge, and the proof that two treatments are effective, comes from two: RECOVERY and a study by the US National Institutes of Health that showed that drug remdesivir Gilead IVs speed up the time it takes for inpatients to recover from Covid-19.
Data collected by AppliedXL and STAT show that the researchers had little interest in studying dexamethasone, the only drug that saves the lives of patients with Covid-19. There have been seven studies of the drug in total, with 13,600 patients, 12,000 of whom were on RECOVERY. Two other steroid drugs, prednisone and methylprednisolone, are being studied in another 2,500 patients.
The hydroxychloroquine experience illustrates how the research company became so uneven and unfocused. In February, hydroxychloroquine was one of several drugs that showed promise in cell culture as a possible antiviral treatment for the virus. Although none of these medications were specifically designed to combat SARS-CoV-2, the coronavirus that causes Covid-19, there was a real reason to hope that one could work as an antiviral treatment to help infected patients or prevent infection. .
The first results from researchers in France sparked interest in the drug in March, even though they were not obtained from a randomized trial. On March 19, President Trump, at a press conference, said that hydroxychloroquine “had shown very encouraging, very encouraging results,” and promised “we will be able to make that drug available almost immediately.” Watchdog group Media Matters said that between March 23 and April 6, Fox News guests and hosts he mentioned medicine almost 300 times.
Generic pharmaceutical manufacturers made huge donations of hydroxychloroquine and chloroquine to a national stockpile of drugs, prompting the Food and Drug Administration to grant emergency use for use in hospitals on March 28.
In early April, 58% of patients hospitalized with Covid-19 were receiving the drug, triple the level in February, according to CarePort Health, which collects drug utilization data from electronic medical records.
Rather than conducting studies that were large enough and well designed to discover whether hydroxychloroquine or chloroquine could prevent or treat Covid-19, many doses went to studies without control groups, essentially tracking the use of the drug in hospitals. .
On Saturday, the World Health Organization said its own large study had found no benefit for either hydroxychloroquine or lopinavir-ritonavir. It is still possible that one of the ongoing studies of hydroxychloroquine shows a benefit, perhaps earlier in the disease.
“The lack of leadership around a clinical trial agenda in the United States is one of the failures of the United States’ pandemic response,” said Walid Gellad, director of the Center for Drug Policy and Prescription at the University of Pittsburgh. “If we had taken the UK strategy from a set of large pragmatic trials, prioritizing recruitment into those trials, we might have all the answers now that we are waiting.”
American investigators quickly rushed into the battle against Covid-19. Apparently what was missing was a general who could lead them in the fight.
Francesco Marconi contributed reporting. Joanna Lin Su contributed images.
