Trump-touted drug’s trials called lacking
Coordinated tests of hydroxychloroquine for COVID-19 later revealed inefficacy, risks
When word surfaced in March that the malaria drug hydroxychloroquine might be beneficial in treating COVID19, more than 50 clinical trials were quickly set up.
Usually, clinical trials involve thousands of patients and dozens of scientists working under the direction of a large research consortium, a drug company or the federal government.
But many of the hydroxychloroquine trials resembled lone-wolf research, overseen by individual hospitals and universities, at times without the typical rigorous research standards.
As a result, a Milwaukee Journal Sentinel analysis found, the trials became a frenzied hodge-podge of undertakings — an unprecedented scientific free-forall in which research overlapped, studies were poorly designed, and patients were given drugs of unproven benefit.
Perhaps most importantly, hydroxychloroquine and other powerful drugs may have exposed patients to potential serious side effects beyond the harm of COVID-19.
These side effects — or “adverse events,” as they are often called in medicine — will likely become an increasingly crucial issue in the coming months as scientists race for COVID-19 treatments and vaccines.
But because of long-standing weaknesses in the U.S. Food and Drug
Administration’s system for keeping tabs of those side effects, the toll may never be fully revealed.
The system has suffered from largescale under-reporting of adverse events for decades. And because reporting is mandatory only for drug companies — not the hospitals that may have been operating the trials — those adverse events don’t have to be reported.
“Given that we can send a spacecraft to Pluto, you would think we would have a better adverse events system,” said G. Caleb Alexander, a drug safety expert and professor at Johns Hopkins Bloomberg School of Public Health.
In the onslaught of COVID-19 trials, many well-intentioned researchers were giving some of the same drugs — hydroxychloroquine and other repurposed medications — to thousands of people, tying up resources in an effort to answer the same questions. Worse, they were doing it in ways that might not accomplish that and could delay the quest to find viable treatments.
Avoiding the go-it-alone approach, the U.K. made some of the most important COVID-19 drug research findings, in part because of coordinated research across its National Health System.
In June, University of Oxford researchers were the first to find a lifesaving drug, the common steroid dexamethasone, which cut the death rate by one-third in COVID-19 patients on ventilators and by 20% in those getting supplemental oxygen. The trial involved more than 6,400 patients across the British health care system.
Earlier, Oxford researchers found that hydroxychloroquine provided no benefit to hospitalized COVID-19 patients. That trial was coordinated across the U.K. in 4,700 patients. That study also found that patients who got the drug were slightly less likely to be discharged from the hospital alive within 28 days and were slightly more likely to need ventilation.
Last month, Oxford researchers also found no benefit from the combination antiviral HIV drug lopinavir-ritonavir in a trial involving 5,000 hospitalized COVID patients. The drugs also were being studied in smaller trials in the U.S. and many others around the world.
Other drugs, same issues
The hydroxychloroquine story is being repeated with dozens of other drugs that have been repurposed to treat or prevent COVID-19, the Journal Sentinel analysis found. More than 400 COVID19 studies were being conducted in the U.S. as of early July, according to the database ClinicalTrials.gov.
The site is maintained by the U.S. National Library of Medicine, part of the National Institutes of Health. Merely listing a trial on the site does not mean it has been evaluated or verified by the federal government.
Even before the pandemic, “there were a lot of silly little trials that were not very good,” said Jerry Avorn, a professor of medicine at Harvard Medical School and an expert in the study of drugs in large numbers of people. With COVID-19 less rigorous trials became more common.
That, in turn, has led to a politicization of science, he said, such as when the FDA used flimsy science to issue an emergency use authorization for hydroxychloroquine on March 28 only to revoke it less than three months later.
President Donald Trump promoted the drug early on, and in May he said he had been taking it to prevent getting COVID-19. Another proponent of the drug, President Jair Bolsonaro of Brazil, revealed this month that he had tested positive for COVID-19 and that he, too, was taking the drug.
So-called off-label use of unproven drugs may seem like the compassionate thing to do, but it is based on the faulty assumption that it will lead to more good than harm, said Andre Kalil, a professor of medicine and infectious disease expert with the University of Nebraska Medical Center. That is especially concerning when someone already is sick from an illness such as COVID-19. Adding unproven drugs could make them worse.
A survey last month by the Heart Rhythm Society, for example, found that 17% of health care professionals in the field reported having patients who used hydroxychloroquine or chloroquine for COVID-19 and who developed an EKG finding that put them at high risk for developing a potentially dangerous heart beat.
There is a belief among some doctors that if a drug is used off-label and the patient dies, it was because of the disease, but if the patient lives it was because of the drug, Kalil said.
“That’s not only not true, it is dangerous,” he said, adding that such findings only can come from controlled research.
Trials set up in ways that limit value
A paper published in June by Alexander and other researchers at Johns Hopkins looked at the first wave of U.S. and international COVID-19 clinical trials. It found that many were set up in a way that will limit their value.
Often they lacked key features that would lead to useful results, such as the use of randomized control groups and placebos, both which help eliminate bias and make the findings more useful. Two-thirds were so-called “open label” trials in which participants and researchers knew who was getting the drug, they found.
“The world has never seen such a complex, jumbled wave of scientific activity,” Alexander said.
Lacking in coordination, the hydroxychloroquine trials used widely different doses, the Journal Sentinel analysis found. About half of all the studies were listed as actively recruiting patients.
Some were set up to test the drug alone, while others included other drugs or vitamins. Some used the preferable, blinded approach in which the patients and sometimes the researchers did not know who was getting the drug or a placebo; some did not. Some used the gold standard, the randomized approach in which participants are divided by chance to eliminate bias; others did not.
At least 12 of the 50 hydroxychloroquine trials analyzed by the Journal Sentinel were open-label trials. At least 24 involved fewer than 1,000 patients.
Most were not large enough to be definitive or added other agents that could confuse the finding.
Trials of 1,000 or more people generally are needed to reach firm conclusions. But a trial in Utah was set up to test hydroxychloroquine on 300 patients; at a Hawaii hospital, 350 patients; and at a hospital in Pennsylvania, 400 patients.
A study in California looked at one day of hydroxychloroquine as a way to prevent COVID-19 in health care workers but also threw in 12 weeks of vitamins C, D and zinc. A hospital in New York studied hydroxychloroquine with zinc and added an antibiotic, either azithromycin or doxycycline.
A Kentucky study tried look at five different potential Covid treatments. It looked at hydroxychloroquine with azithromycin, but also looked at Ivermectin, a drug used to treat roundworm; as well as a Japanese drug that treats an inflamed pancreas; and a Chinese supplement known as sweet wormwood that can be served as tea or coffee.
The U.S. model is to go it alone at times, said Alex Spyropoulos, a professor of medicine at the Zucker School of Medicine at Hofstra/Northwell in New York. “It is an individualist model. They don’t like to play together. In a pandemic it shows its shortcomings.”
But when individual hospitals start their own trials, they run into a morass of legal, ethical and logistical problems that have to be overcome, he said. More importantly, they may not be able to enroll enough patients to make the trial results useful.
Spyropoulos, who is overseeing a clinical trial of anticoagulants in COVID patients, said the intentions were good. Many hospitals were seeing patients “dying left and right” and wanted to do something, but the lack of national coordination meant that resources that went into setting up the trials could have been wasted.
The U.S. government has made contributions in coordinated trials sponsored by the National Institutes of Health.
In a study it sponsored involving 1,100 patients in 10 countries, the agency announced in April that the drug remdesivir allowed hospitalized patients to recover in 11 days on average, compared with 15 days for those who got a placebo.
A couple weeks after Oxford researchers found no benefit with hydroxychloroquine, the National institutes of Health halted a hydroxychloroquine study because of difficulties in enrolling adequate numbers of patients. The end came a little more than a month after the trial was announced and when the lack of utility of hydroxychloroquine had become obvious.
About the same time, a smaller study by the agency concluded there was no benefit from the drug in hospitalized patients.
But the rash of lower quality COVID-19 research has been going on in the U.S. and around the world, according to a new paper in the journal Med.
Regardless of where the research took place, most were single-center trials that were not blinded, making them more susceptible to bias and less likely to be widely applicable, the authors concluded.
The researchers from the University of Texas Southwestern Medical Center looked at 1,029 trials of various COVID-19 interventions that were registered around the world, including 185 in the U.S., between Jan. 23 and May 5. Hydroxychloroquine led the way with 217 trials.
With the devastating impact of COVID-19 across the planet, international collaboration into promising treatments might have been expected, but that was not the case, the researchers found. Less than 3% of the trials involved collaborations across countries.
“It just seems like it was more of a waste of resources,” said lead author David Hsieh, an assistant professor of internal medicine at the university.