FDA’s emergency approval of blood plasma is now on hold

Last week, just as the Food and Drug Administration was preparing to issue an emergency authorisation for blood plasma as a COVID-19 treatment, a group of top federal health officials including Dr. Francis Collins and Dr. Anthony Fauci intervened, arguing that emerging data on the treatment was too weak, according to two senior administration officials.

The authorisation is on hold for now as more data is reviewed, according to H. Clifford Lane, the clinical director at the National Institute of Allergy and Infectious Diseases. An emergency approval could still be issued in the near future, he said.

Donated by people who have survived the disease, antibody-rich plasma is considered safe. President Donald Trump has hailed it as a “beautiful ingredient” in the veins of people who have survived COVID-19.

But clinical trials have not proved whether plasma can help people fighting the coronavirus.

Several top health officials — led by Collins, the director of the National Institutes of Health; Fauci, the government’s top infectious disease expert; and Lane — urged their colleagues last week to hold off, citing recent data from the country’s largest plasma study, run by the Mayo Clinic. They thought the study’s data to date was not strong enough to warrant an emergency approval.

“The three of us are pretty aligned on the importance of robust data through randomised control trials, and that a pandemic does not change that,” Lane said in an interview Tuesday.

The drafted emergency authorisation leaned on the history of plasma’s use in other disease outbreaks and on animal research and a spate of plasma studies, including the Mayo Clinic’s program, which has given infusions to more than 66,000 COVID-19 patients thanks to financing from the federal government.

An FDA spokeswoman declined to comment.

Plasma, the pale yellow liquid leftover after blood is stripped of its red and white cells, has been the subject of months of intense enthusiasm from scientists, celebrities and Trump, part of the administration’s push for coronavirus treatments as a stopgap while pharmaceutical companies race to complete dozens of clinical trials for coronavirus vaccines.

Emergency authorisations, which do not require the same level of evidence as a full FDA approval would, have been a fraught subject for the government during the pandemic. The agency gave one to the malaria drugs hydroxychloroquine and chloroquine only to rescind it months later after the drugs were found to be ineffective against the coronavirus, and potentially harmful. An emergency authorisation for blood plasma would most likely ease the clerical burdens on hospitals in conducting infusions.

Senior health officials have privately expressed concern about the rapid growth of the Mayo program and the perceived rush to declare plasma effective without the affirmation of results from randomised trials, which scientists have long relied on as the gold standard of evidence. Skyrocketing enrolment in the program has prompted a debate among researchers about what kind of empirical certainty is needed in treating patients in a public health emergency.

An emergency approval now would “change the way people view trials,” said Dr. Mila B. Ortigoza, an infectious disease specialist at NYU Langone Health who started a trial with colleagues at Montefiore Medical Center.

“We want to make sure that when we say it works, we are confident, with indisputable evidence,” she said. “We’re dealing with patients’ lives here.”

Unlike the malaria drugs, plasma, which has been used since the 1890s to treat infectious diseases, has earned the attention of a highly credentialed community of microbiologists and immunologists eager to prove its usefulness. The Mayo Clinic has already published analysis on tens of thousands of patients in its expanded access program showing that plasma is safe.

The most recent batch of data from the program included more than 35,000 COVID-19 patients, many of them in intensive care and on ventilators, and suggested that plasma administered within three days of a diagnosis reduced mortality rates. When calculated a month after the infusions, the death rate of patients who received plasma within three days of diagnosis was lower (21.6%) than it was for those who received plasma later (26.7%).

But the study did not have a control group of patients given a placebo to compare with those given plasma, making it difficult for scientists to assess whether the treatment really worked. And given the limited supply of plasma, it is not clear how realistic treating patients within three days of diagnosis would be.

The program’s enrolment has surged to more than 30 times as high as initially expected, complicating the ability of scientists to recruit sick patients to randomised trials.

It “ballooned to a degree that, you know, is becoming unmanageable,” Lane said.

Statisticians at the FDA are now examining the Mayo data to better understand what factors other than the treatment might have influenced patient responses, such as higher-quality care in the hospital, Lane said.

A research team from Houston Methodist hospitals also published preliminary results from a plasma trial last week. Their study of hospitalised COVID-19 patients in the American Journal of Pathology reported that a group of 136 patients who received the treatment were more likely to be alive four weeks later compared with 251 patients who did not receive it. That study found a statistically significant benefit only when patients were treated within three days of admission and when the plasma contained a high concentration of antibodies.

The Houston study was not randomised, meaning that all of the patients enrolled received the treatment and none received a placebo. (The researchers later compared their outcomes to records from other COVID-19 patients who were not in the study but were matched to be similar to them.)

A surge in cases in Texas this summer quickly brought the hospital system to its enrolment cap, and doctors there have not been able to provide the experimental treatment since mid-July. If the FDA gave an emergency authorisation, doctors at the hospital could possibly begin administering it again, said Dr. Eric Salazar, the study’s principal investigator.

But an emergency authorisation could have the unintended effect of making it harder for rigorous clinical trials to definitively show whether plasma works. Scientists have struggled to recruit patients for randomised trials, as many patients and their doctors — knowing they could get the treatment under the Mayo program — have been unwilling to risk receiving a placebo.

Last month, one such trial in the Netherlands was stopped when researchers realised that patients given plasma showed no difference in mortality, length of hospital stay or disease severity compared with those given a placebo. Most of the patients had already developed their own antibodies by the time they entered the study, the researchers noted.

At least 10 randomised trials in the United States have collectively enrolled only a few hundred people. They have also been stymied by the waning of the virus outbreak in many cities, complicating the ability of researchers to recruit sick people. Collins has encouraged a strategy of pooling the results from randomised trials, an idea that has met resistance from some researchers.

Dr. R. Scott Wright, who is helping oversee the Mayo Clinic’s plasma program, was an early proponent of conducting randomised trials. But he said in a recent interview that the mechanics of setting up large studies were complicated by early shortages of plasma, coordination via videoconference calls and the difficulty of predicting where the virus would spread next.

If the FDA does grant the emergency authorisation, it could make it even harder to get answers, said Ortigoza of NYU.

“We will keep going, because we’re in desperate need of a randomised placebo-controlled trial for convalescent plasma,” she said. “This is something our country and the world really needs right now.”

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