These scientists are still studying the world’s most controversial drug, but they can’t find enough people to take it

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BuzzFeed News; John Phillips / Getty Images

When Nicholas White decided to start a clinical trial on hydroxychloroquine, he did not know he had chosen the most controversial drug in the world.

At the start of the pandemic, his research team undertake to see whether the antimalarial medicine could prevent coronavirus infections, which test-tube research has alluded to. Their objective: to recruit 40,000 health workers.

The count, since April: around 100.

Months ago, trials like this were inundated with volunteers hungry for hydroxychloroquine. Just as quickly, his moment passed away. At least four prevention trials have struggled to find enough people willing to follow it, falling short of their collective goal of recruiting tens of thousands of participants, BuzzFeed News found. Their uncertain fate shows how science has become more politicized than ever. But it also makes it clear that drug research is a chaotic mess.

White, professor of tropical medicine at Mahidol University in Bangkok, never imagined that President Donald Trump would baselessly call hydroxychloroquine a “game changer,” or that a fraudulent study would cast a veil on the ground. But neither did he foresee that, in the face of one of the pandemic’s most pressing priorities – finding safe and effective treatments – the scientific community’s response would be so disorganized as to waste time, funding and, perhaps more importantly, willing participants. .

The result is paradoxical: hydroxychloroquine was one of the most studied drugs this spring, and study after study showed that this is not an effective treatment for sick patients. But scientists still don’t know, and may never know if it works as a prophylaxis that prevents infections.

“The fact that it’s August and it’s still an open question is embarrassing,” Walid Gellad, who heads the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, told BuzzFeed News.

Bad publicity certainly didn’t help. Some participants who chose to drop out of the trials told researchers that they believed the drug to be universally dangerous, although that was not entirely true. Safety concerns have been raised about its effects on COVID-19 hospital patients, as well as on top high doses of his sister, chloroquine.

The deeper systemic problem is that there have only been a handful of large and rigorous trials for hydroxychloroquine or, for that matter, for any potential treatment. These randomized controlled trials, in which some people receive treatment and others receive a placebo, are the gold standard in medicine for determining whether a drug works.

In the near absence of coordination between national and global health agencies, separate groups of scientists have conducted smaller and less definitive trials. And for months, the FDA cleared hydroxychloroquine to be administered to patients with COVID-19 outside of clinical trials. This further depleted the pool of people who might be willing to sign up for a trial and risk getting a placebo, in turn blurring the evidence on what worked and what didn’t.

History is repeating itself now with convalescent plasma – the fluid in the blood that remains when blood cells are shed. The plasma of coronavirus survivors contains antibodies that the first studies suggest could help others fight infections. But no randomized trial has proven this so far, or answered crucial questions like which dose works best or on which patients, and studies struggle to recruit enough people. Now it will probably be even more difficult for them to find volunteers, because the FDA has just authorized hospitals to treat patients with COVID-19 with plasma.

White and his colleagues are frustrated, to say the least. Hydroxychloroquine, they complained in a press release this month, was “to be thrown prematurely in the prevention of COVID-19. Two recent prevention studies have come out negative, but outside experts say they’re not the last word.

“I would have liked to see real coordination to do some big final testing, and I think it could have happened,” White, who is also affiliated with the University of Oxford, told BuzzFeed News. “This is not the case.”

It is not known what will happen to the study of his team, who, along with two other institutions, share a $ 20 million grant major funders like the Bill and Melinda Gates Foundation, the Wellcome Trust and Mastercard. “I don’t know if the drug is working or not, I really don’t know,” White said. “But what I do know is we don’t know if it works, and I also know we really need to find out.”

Pete Marovich / Getty Images

FDA Commissioner Stephen Hahn watches as President Donald Trump announces that the FDA has issued emergency clearance for blood plasma as a treatment for the coronavirus.

When a mysterious, a deadly pathogen began to spread beyond China’s borders this winter, as scientists around the world embarked on a desperate search for cures. A cure from scratch would take precious time, so they scoured the literature for a drug that already existed for other conditions, which might also be able to tackle this new coronavirus.

Hydroxychloroquine quickly rose to the top of the list. Approved in the United States since the 1950s, it is a less toxic version of the antimalarial drug chloroquine, also used for lupus and rheumatoid arthritis. In early spring, laboratory studies indicated that he could inhibit SARS-CoV-2 in infected cells. Some researchers have argued for give it a shot as a preventive measure.

“There was nothing else that was really potent against coronaviruses, SARS-CoV-2 in particular,” White said. “These drugs are inexpensive, widely available, can be deployed immediately and safely.”

Ruanne Barnabas of the University of Washington said her motivation for conducting a prevention study – unrelated to White – was to answer the question one way or another. She feared that India started using hydroxychloroquine as a preventive measure without solid evidence.

“It’s not a good use of resources if it doesn’t work,” said Barnabas, associate professor of global health and medicine. “We should be focusing on every dollar spent. We needed a clear answer here for hydroxychloroquine for prevention purposes. “

They weren’t the only ones studying drugs. By July, scientists had designed 1,200 trials to study treatment or prevention for COVID-19 – and one in six involved hydroxychloroquine or chloroquine, according to a Stat analysis. Likewise, the researchers reported that nearly a quarter of randomized trials linked to coronaviruses this spring involved a drug from the chloroquine family. They have been studied in high and low doses, taken alone and in combination with vitamins and antibiotics, and in all kinds of patients.

But almost from the start, the drug buzz was confusing, politicized, and seemingly contradictory. In March, a French scientist touted hydroxychloroquine as a treatment for coronavirus based on a small study widely condemned. Trump then pressured the FDA to allow it, at some point would have take it himself, and people rushed to collect it. Then the FDA warned that it could cause irregular heart rhythms in hospitalized patients.

In another puzzling twist, an explosive study published in The Lancet in May linked hydroxychloroquine to higher risk of death – only to be later revealed as fraudulent and obtain retracted. Even so, British researchers reported in June that a massive trial showed no benefit, leading the FDA to withdraw his authorization.

Meanwhile, a handful of scientists were still trying to determine whether hydroxychloroquine could prevent infections. But the participants were increasingly difficult to find. As a precaution following the Lancet study, the World Health Organization discontinued a trial with hydroxychloroquine it worked, and White did too, putting his research back several weeks.

In April, a study conducted by the Duke Clinical Research Institute set out to enroll 15,000 health workers. Now they are hoping for 2,000. With around 1,240 enrolled in mid-August, they still do not have enough staff.

“Our highest enrollment was in our second week,” said Susanna Naggie, a Duke teacher overseeing the study. She predicted the numbers would have continued to rise, but “that just didn’t happen.” She blamed the constant comments from politicians and the media – “every story bent slightly to this audience’s preference.”

the prevention study at the University of Washington Currently has more than 800 health workers, with a target of 2,000. Recruitment since the end of March has been “regular,” Barnabas said, although “affected by the news cycle from time to time.”

A team of researchers from the University of Minnesota and Canada conducted two prevention studies. The second started recruiting in April, when hydroxychloroquine was no longer in the news. “People went from who wanted to try this drug to no one wanted anything to do with it,” said study leader Radha Rajasingham, assistant professor of infectious diseases and international medicine.

Although she declined to discuss the results because they are yet to be released, she admitted that they would not be conclusive due to their sample size. Registrations reached just under 1,500 people, or less than half of the initial target of 3,200. “We stopped our registration prematurely because very few people registered at the end, due to the negative press, ”she said.

From the start, she says, the drug was controversial on both right and left.

“It used to be that people felt it was unethical for us even to study this,” Rajasingham recalls. “They felt it was obvious that hydroxychloroquine was working. Another group felt it was unethical for us to study this because it clearly was not working. “

White admitted it was no surprise that people were reluctant to participate in prevention trials for the drug.

“I can understand that the general public is a little confused and suspicious,” he said. “I would be too.”

George Frey / Getty Images

A pharmacy technician counts hydroxychloroquine tablets at Rock Canyon Pharmacy in Utah.

Despite the overabundance Of the trials with hydroxychloroquine, only a few have been large enough to produce strong evidence of its effectiveness. The UK’s Recovery trial, which in June found the drug to be an ineffective treatment for coronavirus patients, is widely considered the most robust.

It was one of many potential COVID-19 therapies being tested across the country. In more encouraging news, the recovery trial also revealed that the steroid dexamethasone reduces the number of deaths by up to a third in patients on ventilators.

Due to the large number of participants tested, these results were taken seriously. The latest trial reported that it had recruited more than 11,800 patients from more than 175 hospitals, making it the largest randomized trial on COVID-19 in the world. In its hydroxychloroquine arm alone, 1,500 people received the drug and compared to more than 3,000 who received standard hospital care.

Nothing like this has happened in the United States. “More than 100 separate groups have decided to do 100 separate trials on hydroxychloroquine,” said Derek Angus, president of critical care medicine at the University of Pittsburgh. “Nobody needs 100.”

The main difference comes down to this: unlike the UK, where the National Health Service can coordinate clinical research through its extensive network of public hospitals, research in the US is not designed to function as a whole. coherent. In the system as it was designed, warring factions – drug companies, academic medical centers, individual scientists – are looking for money for their own trials.

“And so when there’s some sort of existential crisis and the whole world needs to come together to generate information as quickly as possible,” Angus said, “it turns out no one has a mechanism. to promote cooperation. “

There are a few exceptions. The prevention study conducted by Duke is funded by the Institute for Patient-Centered Outcomes Research, which is recruiting participants from a network of 30 research sites across the country.

NIH-sponsored clinical trials have also been conducted in medical centers nationwide, finding benefits for the antiviral remdesivir and yet another negative result for hydroxychloroquine as a treatment.

Even so, these two trials involved around 1,500 patients – a fraction of the recovery trial. As Angus, who helped run the NIH’s hydroxychloroquine trial, put it, “Every step of the process isn’t really designed for speed.”

Which means that some trials are still in progress. To date, the ClinicalTrials.gov database is littered with planned hydroxychloroquine studies around the world. As of mid-August, at least 80 trials to study it as a treatment for COVID-19 or conditions caused by it were listed as planned or active. (BuzzFeed News couldn’t verify how many were actually in progress.)

Theoretically, this research could go on indefinitely – studying different doses, starting at different times and for different durations, or in combination with other treatments. But “in a world where we have limited resources, you can’t do every possible scenario for every drug,” said David Fajgenbaum, assistant professor of medicine at the University of Pennsylvania.

Many researchers agree that, at least as a treatment, hydroxychloroquine is over. Paul Garner, professor at the Liverpool School of Tropical Medicine, coordinates the Cochrane review of all research on the drug’s effectiveness. This analysis is not yet complete, but Garner said, “I haven’t seen a single piece of evidence, from my observation, of any benefit.”

Donald Berry, a biostatistician at the MD Anderson Cancer Center and clinical trials consultant, is very skeptical that prevention will be another story.

“If there’s a trial going on with hydroxychloroquine for prevention, you really must be asking yourself, ‘Why am I doing this? “There are billions of therapies in the world, why hydroxychloroquine?”

He has a point. So far, two trials have shown that hydroxychloroquine does not appear to prevent coronavirus infections in people who take it soon after exposure.

Outside researchers say these results are not definitive. In one of the studies, involving 2,300 people in Barcelona, ​​participants were told about the treatment they were receiving, which could have skewed the results. And the 800 or so people in the other – which was led by Rajasingham and his colleagues at the University of Minnesota – have not been tested uniformly for the disease.

These studies also tested the drug as a preventative measure after someone was exposed, but before they got sick. Other researchers are now studying what happens when people take hydroxychloroquine before exposure. But it is not known if they will get answers.

White realizes that his trial will likely not end by the end of the year as planned, if ever.

“We are determined to try. I don’t know if we will be successful, ”he said. “It’s kinda sad that the most talked about drug in the world for six months, we just don’t know if it works or not.” ●

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