As Trump praises plasma, researchers struggle to finish critical studies

An American Airlines flight took off from La Guardia Airport in New York last Wednesday morning, carrying 100 pouches of blood plasma donated by COVID-19 survivors for delivery to Rio de Janeiro. American scientists are hoping COVID-19 patients in Brazil will help them answer a century-old question: Can this golden serum, loaded with antibodies against a pathogen, actually heal the sick?

The truth is that no one knows if it works.

Since April, the Trump administration has funnelled $48 million into a programme with the Mayo Clinic, allowing more than 53,000 COVID-19 patients to get plasma infusions. Doctors and hospitals desperate to save the sickest patients have been eager to try a therapy that is safe and might work. Tens of thousands more people are now enrolled to get the treatment that has been trumpeted by everyone from the president to actor Dwayne Johnson, better known as The Rock.

President Donald Trump on Monday promoted its promise: “You had something very special. You had something that knocked it out. So we want to be able to use it,” he said, calling on COVID-19 survivors to donate their plasma, which he called a “beautiful ingredient.”

But the unexpected demand for plasma has inadvertently undercut the research that could prove that it works. The only way to get convincing evidence is with a clinical trial that compares outcomes for patients who are randomly assigned to get the treatment with those who are given a placebo. Many patients and their doctors — knowing they could get the treatment under the government program — have been unwilling to join clinical trials that might provide them with a placebo instead of the plasma.

The trials have also been stymied by the waning of the virus outbreak in many cities, complicating researchers’ ability to recruit sick people. One of those clinical trials, at Columbia University, sputtered to a halt after the outbreak subsided in New York. One of its leaders, Dr W Ian Lipkin, looked for hospitals in other hot spots in the United States to continue the work. But he found few takers.

“Without a randomised control trial, it’s very difficult to be certain that what you have is meaningful,” he said.

As of last week, just 67 people had enrolled in the Columbia study — too few to form sound statistical conclusions. In a last-ditch effort, Lipkin’s team shipped the plasma to Brazil, where the epidemic is still raging.

Now, at the height of a public health crisis, the government’s push to distribute an unproven treatment to desperately ill patients as quickly as possible could come at the cost of completing clinical trials that would potentially benefit millions around the world by determining whether those treatments actually work.

In a statement, a spokeswoman for the Food and Drug Administration said that the expanded access program was meant to bridge the gap until trials could get underway and “was never intended to substitute for randomised clinical trials, which are critically important for the demonstration of efficacy.”

The FDA is preparing an emergency authorization to use the treatment, according to scientists who have been briefed on the plans. The policy would ease the clerical burden on hospitals to get clearance for transfusions, further hampering clinical trials, researchers said. An FDA spokeswoman declined to comment on whether such an authorisation was in the works.

The move would mean the FDA is “yielding to political pressure,” said Dr Luciana Borio, who oversaw public health preparedness for the National Security Council under Trump and who was acting chief scientist at the FDA under President Barack Obama.

“I’m not as concerned about the political leaders having a misguided approach to science,” she said. “What I’m really concerned about is scientists having a misguided approach to science.”

On Monday, four former FDA commissioners — including Dr Scott Gottlieb, who served under Trump — called for more rigorous clinical trials to evaluate whether plasma is an effective treatment for the coronavirus. “If this is going to work, we need to do it right,” they wrote.

Convalescent plasma, the pale yellow liquid that’s left after blood is stripped of its red and white cells, has been used since the 1890s to treat infectious diseases, including the flu, severe acute respiratory syndrome and Ebola. Scientists believe it may work by giving sick patients the antibodies of those who have recovered from the infection.

Plasma’s potential benefits are also promoted on conservative talk shows, as was hydroxychloroquine, a treatment for malaria that was enthusiastically embraced by Trump but had not been found effective against the coronavirus in recent clinical trials.

Unlike hydroxychloroquine, which has potentially harmful side effects, plasma was seen as safe and top medical researchers had enthusiastically set out to study it as American hospitals filled with COVID-19 patients.

“We are in a medical crisis — we don’t have alternatives,” said Dr Arturo Casadevall, a microbiologist at Johns Hopkins University who is the chair of the National COVID-19 Convalescent Plasma Project, a consortium coordinating research into the therapy.

But at least 10 randomised, placebo-controlled trials in the United States have enrolled only a few hundred people. And now, seven months into the health crisis, some scientists say the FDA’s programme has undermined their efforts to get answers about plasma’s utility.

“I’ve seen other people describe it as liquid gold,” said Dr Richard Kaufman, medical director of the transfusion service at the Brigham and Women’s Hospital in Boston, where he is the principal investigator of a trial that had intended to enrol 220 patients but has enrolled only one. “I would say I have a lot of uncertainty at this point.”

A Century of Experimentation

Antibodies have been tapped to heal the sick since at least the 1890s, when doctors used the serum of animals to treat diphtheria, a dangerous bacterial disease. Convalescent plasma was used during the 1918 flu pandemic, and so-called serum therapy became a treatment for everything from pneumonia to measles. In 1925, teams of sled dogs travelled  hundreds of miles over ice to deliver serum to the Alaskan town of Nome, which was battling a diphtheria outbreak.

Although it fell out of favour in the 1940s with the discovery of antibiotics, convalescent plasma is often the first tool that doctors use when they are desperate to treat an emerging epidemic.

So when the coronavirus began spreading this year, doctors in Wuhan, China, as well as in Iran and Italy turned to the old standby.

Casadevall became one of its earliest US backers, writing an opinion piece in The Wall Street Journal in February and calling colleagues from his Baltimore living room to encourage its study.

By late March, as deaths from the virus rose, Mount Sinai Hospital in New York and Houston Methodist in Texas began transfusing patients with plasma.

As the outbreak spread across the United States, calls grew to expand distribution of plasma. But hospitals could use the plasma on a limited number of patients only if they received emergency approval from the FDA. Every day beginning in March, the agency heard from the doctors of hundreds of patients asking for permission to try plasma, according to a spokeswoman for the agency.

A loosely organized group of doctors, including Casadevall, began pushing for a more coordinated approach. On April 3, the FDA and the Mayo Clinic opened the “expanded access” programme, using plasma donated through the American Red Cross.

Extracting plasma is cumbersome. It begins much like a blood donation, with a needle inserted into a vein. The blood is drawn into a machine with a centrifuge, which filters the plasma and returns the rest of the blood to the body. The plasma must be stored at freezing temperatures. It cannot be mass produced.

Dr R Scott Wright of the Mayo Clinic, who is helping to run its plasma programme, said he was an early advocate for conducting randomised trials of convalescent plasma. But the mechanics of setting up large studies were complicated by early shortages of plasma, coordination via Zoom and the difficulty of predicting where the virus would spread to next.

Still, researchers at major medical centres in the Northeast began setting up studies. Dr Mila B Ortigoza, an infectious disease specialist at NYU Langone Health, started a trial with colleagues at Montefiore Medical Centre in just weeks, enrolling its first patient on April 17 and condensing years of work into days. But by the time it got started, the pandemic was easing.

“The curve got squashed here in New York,” said Dr Elliott Bennett-Guerrero, the leader of another randomised trial of plasma at Stony Brook Medicine on Long Island. He said the hospital had enrolled only about 80 of the 500 planned participants. The trial is now stalled.

And the Mayo Clinic’s expanded access programme exploded.

“We initially thought that we would enrol 3,000 people,” said Dr Michael Joyner, the scientist leading the effort. Casadevall was so inundated with inquiries from patients’ families asking about plasma that he removed his personal email from the Johns Hopkins website.

By June, 20,000 people had received plasma, and the program released a promising report on the method’s safety. But there was no control group for comparison, so the study could not evaluate whether the treatment did any good.

And yet, the treatment is now more popular than ever. Alex M Azar II, the secretary for health and human services, told governors on a call Monday that demand for plasma was outstripping supply.

Randomized trials outside the United States have not been able to prove plasma’s effectiveness, either. A trial at seven medical centres in Wuhan, the likely ground zero for the virus, concluded that convalescent plasma did not significantly improve patients’ recovery time.

As in the US trials, the Wuhan study had trouble recruiting participants and concluded early with just 103 volunteers. An analysis recently conducted by researchers, including Joyner and Casadevall, found that several overseas studies hinted that plasma was effective, but not all of them were randomised.

An Opening for Trump

The Trump administration has framed convalescent plasma as a rare bright spot in the pandemic.

Eager to present his administration as marching toward a “cure,” Trump has mentioned plasma alongside remdesivir and dexamethasone, two coronavirus treatments that have been shown to be effective in randomised trials.

Dr Deborah L Birx, the leader of the White House’s coronavirus task force, at one point pushed for the federal government to secure 500,000 bags of plasma to store for a possible wave of infections in the fall, according to a senior administration official. She also pushed for plasma transfusions in nursing homes, the official said.

When asked about these claims, a task force official said that Birx wanted to move quickly to capitalize on the period of time after a person is infected, when their plasma contains higher antibody levels. Birx said she wanted clinical trials to include vulnerable people in nursing homes, the official added.

Dr Stephen M Hahn, the FDA commissioner, began discussing the benefits of plasma at White House briefings in March. In interviews and congressional testimony since then, he has presented it as one of the few therapeutics the agency can publicly endorse.

Last week, he said the FDA was “encouraged by the early promising data that we’ve seen and that it was “studying these data to determine, ultimately, the safety and efficacy of this product.”

But he added that if plasma “doesn’t turn out to be the treatment we think it might be, remember that your donations still count with the American Blood Centres and the American Red Cross.”

The treatment has the backing of celebrities like songwriter Dolly Parton, who is financing a randomized trial at Vanderbilt University Medical Centre in Nashville, and Johnson, who recorded a video pleading with survivors to donate blood.

“The plasma that’s in your blood can literally save lives,” he says in the message. “But we have to act fast.”

Joyner said that Mayo researchers were preparing to publish a more detailed analysis of the data they had collected through the access programme. But he said even he was not sure of the FDA’s plans for the expanded access programme.

There is also an effort underway, led by New York medical institutions, to pool the data of unfinished trials, a strategy encouraged by Dr Francis Collins, the director of the National Institutes of Health. “It is a really, really powerful approach,” said Dr Liise-anne Pirofski, the chief of infectious diseases at Albert Einstein College of Medicine and Montefiore Medical Centre  who is leading the clinical trial with Ortigoza.

But that idea, said Kaufman of Brigham and Women’s Hospital, is less than ideal. He said he did not plan to participate. “I worry about combining partially finished studies that really may be different,” he said.

Some of the trial investigators, like Lipkin, are finding new sites where they hope to complete their work. NYU Langone is expanding to hospitals in Connecticut, Florida and Texas. And researchers at Johns Hopkins have begun two trials of convalescent plasma in people who are not yet sick enough to be hospitalised, testing the theory that the treatment might work best earlier in the infection.

Casadevall said that he still believed randomized trials were the “only way we’re going to know whether it works or not,” but that they should not be put in opposition to Mayo’s programme.

“These things can always be second-guessed afterwards,” he said. “But given the likelihood that it would work and given the history of safety, it was worth trying it as a compassionate use. Maybe you can do this in an emergency and still walk out with efficacy data.”

Lipkin said that, in retrospect, he might have played a role in shaping plasma’s fame, unknowingly undermining his own trial. In March, he appeared on television shows like “Lou Dobbs Tonight” on Fox News, where he extolled its potential benefits — a move that, he speculates, could have led administration officials to move more quickly to expand access.

“I share some responsibility for this,” he said. “I think there are all kinds of arguments one can make based on history, having a precedent. But that’s not a substitute for rigorous science.”

c.2020 The New York Times Company